METHODS AND MODIFICATIONS THAT PRODUCE ssRNAi COMPOUNDS WITH ENHANCED ACTIVITY, POTENCY AND DURATION OF EFFECT

ABSTRACT

Compositions and methods for down modulating expression of target nucleic acids using a single strand oligoribonucleotide siRNA compound are disclosed.

This application claims priority to U.S. Provisional Application No.61/987,448 filed May 1, 2014, the entire contents being incorporated byreference herein.

FIELD OF THE INVENTION

This invention relates to the fields of RNAi, oligonucleotide basedtherapeutics, medicine, drug development and functional genomics byproviding novel means to modulate nucleic acid expression and/orfunction, particularly mRNA as well as coding and non-coding regulatoryRNA. More specifically, the invention provides novel RNAi guide strandscomprising modifications that enhance interactions with the RNAimechanism within the cell and methods of use thereof for modulatingexpression of target genes and nucleic acids of interest.

BACKGROUND OF THE INVENTION

Numerous publications and patent documents, including both publishedapplications and issued patents, are cited throughout the specificationin order to describe the state of the art to which this inventionpertains. Each of these citations is incorporated herein by reference asthough set forth in full.

RNA interference (RNAi) refers to a set of overlapping cellularmechanisms (RNAi mechanisms) typically involvingin double stranded RNA(dsRNA) structures (RNAi triggers) which activate and direct the RNAimechanism to particular nucleic acid targets on the basis ofcomplementary base pairing. The RNAi mechanism then causes a modulationof the expression and/or function of the target(s). In most instancesthe nucleic acid targets are RNA (often mRNA) but coding and non-codingregulatory RNA can also be targeted. In addition, some RNAi triggers candirect an RNAi mechanism to certain DNA targets, such as the enhancer,silencer and/or promoter elements of particular genes, resulting in amodulation of the activity of the gene.

RNAi triggers are typically in the range of 21-23 nucleosides in length.Only one of these strands, called the guide strand or antisense strand,directs the RNAi mechanism to the target(s). The complementary strand tothe guide strand in the RNAi trigger is called the passenger or sensestrand. The passenger strand is discarded during the activation of theRNAi mechanism.

Two main categories of RNAi triggers have been distinguished: smallinhibitory RNA (siRNA) and microRNA (miRNA). Both of these are generatedfrom longer precursor dsRNA by the enzymatic capability of Dicer. In thecase of siRNA, the original source of the dsRNA can be exogenous to thecell or it can be derived from transposable elements or certain viruseswithin the cell. In contrast, miRNA is produced from precursor moleculesthat are typically generated from independent genes or from intronsequences. Unlike siRNA, miRNA broadly inhibits multiple differenttargets, typically different mRNAs.

The differences between siRNA and miRNA are reflected, in part, by thespecific “targeting codes” that are associated with them. The targetingcode can be briefly defined as the subset of the guide strand sequencethat directs the RNAi mechanism to the target to be engaged and thenmodulated. Ambros et al. (RNA 9: 277-9, 2003) and Griffiths-Jones et al.(Nucleic Acids Res 36: D154-8, 2007) provide a more detailed descriptionof how naturally occurring siRNA and miRNA can be distinguished andannotated.

The general RNAi mechanisms that underlie the implementation of siRNAand miRNA based effects are substantially overlapping, but theparticulars of how siRNA vs. miRNA based RNAi mechanisms modulate targetexpression and/or function are substantially different. At the heart ofthe general mechanisms applicable to both of these types of RNAi triggeris the RNA-induced silencing complex (RISC). The siRNA or miRNA isloaded into RISC typically with the help of the RISC loading complex(RLC) that commonly includes Dicer. During the activation of the RNAimechanism by an RNAi trigger, the passenger strand is discarded and theguide strand is used to direct RISC to its target(s).

A guide strand that is separated from the passenger strand isnon-covalently bound throughout most or all of its length to a member ofRISC that is typically one of four argonaute proteins (AGO-1-4). Anyargonaute protein can engage any RNAi trigger guide strand, miRNA orsiRNA, but in humans only AGO-2 has intrinsic enzymatic activity whichcan cleave the RNA target. Guide strands from siRNA triggers engaged byAGO-2 or another argonaute can also result in target modulation byinducing a steric hindrance effect rather than target cleavage. Further,any of the argonautes can engage a miRNA guide strand that subsequentlydirects RISC to its targets. Tuschl's group first reported theadministration of synthetic siRNA against mRNA targets of choice tocells (Elbashir et al., Nature 411: 494-498, 2001). This success lead toa greatly increased interest in manufacturing siRNA drugs based onnatural RNAi triggers to treat a variety of diseases. The continuingbottleneck that prevents the broad use of such drugs in the clinic,however, is their requirement for a carrier that can greatly increasethe efficiency with which the double strand siRNA or miRNA drug crossesthe surface membrane of cells in the body. Despite a great effort thereis still an absence of any individual or any set of carriers capable ofachieving this for a wide variety of tissues and cell types (Aliabadi etal., Biomaterials 33: 2546-69, 2012; Kanasty et al., Mol Ther 20:513-24, 2012).

Administration of siRNA and miRNA drugs, however, has very recentlyreached the stage where a therapeutically useful level of RNAi activitycan be achieved in the livers of humans. Given the natural function ofliver that involves the uptake, processing and elimination of a varietyof substances from the body, the liver is particularly well suitedcompared to other organs/tissue/cell types for carrier-mediated uptakeof large drug molecules such as double strand RNAi drugs.

miRNA is a fundamentally more complex area of RNAi than siRNA andconsequently, attempts to acquire miRNA candidates for therapeutic usehave lagged behind. Potential miRNA-related therapeutics includes miRNAinhibitors and miRNA mimics. Most advanced is the use of antisenseoligos with a steric hindrance mechanism to inhibit the function ofcertain miRNAs. Since these antisense oligos are single stranded, theydo not require a carrier to get into cells in the body and inhibitoryactivity is not limited to the liver. One example is a mixed LNA/DNAphosphorothioate oligo that inhibits miR-122. It has completed phase IItesting with promising results (Janssen et al. N Engl J Med 368:1685-94, 2013). miR-122 is highly expressed by liver and is required forHCV production and it increases the level of total cholesterol inplasma. Steric hindrance antisense oligos require higher doses andhigher affinity for their target compared to RNase H1 dependentantisense oligos or to siRNA (Elmen et al., Nature 452: 896, 2008;Lanford et al., Science 327: 198, 2010).

One solution to the inability to get double strand RNAi drugs into thevarious tissue/cell types in the body is to use single strand RNAidrugs. This has been achieved by sequentially administering drugs(seqRNAi) to subjects that correspond to the passenger and guide strandsof double strand drugs (WO 2011/046983; WO 2012/145729). Anotherpossibility is the use of guide strand only drugs (ssRNAi). These wouldhave the advantage of having simpler dosing schedules that do notrequire the administration of a different second drug, corresponding tothe passenger strand, in order to obtain the desired RNAi effect on thetarget in the body.

The compositions, methods and uses for providing the best ssRNAicompositions known in the art for in vitro and in particularly for invivo use, however, have shortcomings, such as inadequate potency, thathinder their clinical and commercial use. These compositions, methodsand uses (newer ssRNAi) are described in Haringsma et al., Nucleic AcidsRes 40: 4125-37, 2012; Yu et al., Cell 150: 895-908, 2012; Chorn et al.,RNA 18: 96-804, 2012; Lima et al., Cell 150: 883-94, 2012; WO2011/046983; WO 2011/139699; WO 2011/139702; and WO 2012/027206. Inaddition, possible alternatives to the 5′-VP phosphate analog conjugatedto the 5′end terminal nucleoside in the ssRNAi compounds found in Limaet al. (2012) and Yu et al., (2012) were evaluated by the same group andreported in Prakash et al., Nucleic Acids Res 43: 2993-3011, 2015. Noneof the tested alternatives to 5′-VP by Prakash et al., however, provideda better outcome against the intended target compared to compounds with5′-VP when the various ss-siRNAs were evaluated in mice.

Theses compounds are, however, a substantial improvement over the ssRNAipreviously known in the art in that they allow effective ssRNAicompounds to be routinely generated for a variety of targets. This wasachieved by providing for adequate basic nuclease resistance in thessRNAi in a manner that does not eliminate the possibility of obtainingRNAi activity.

The best of these newer ssRNAi compounds require an enveloping carrierfor added nuclease protection in extracellular fluids when used inanimals and were generated by Haringsma et al., (Nucleic Acids Res 40:4125-37, 2012) and Chorn et al., (RNA 18: 96-804, 2012). These compoundsare 21-mers that have the following modifications: (1) A phosphateconjugated to the 5′ carbon of the 5′-end nucleoside sugar(5′-phosphate); (2) 2′-O-methyl (2′-O-Me) uridines in nucleotidepositions 20 and 21; (3) 2′-fluoros in positions 1-19; and (4) Onlyphosphodiester linkages.

Using this modification pattern two ssRNAi compounds targeting differentsites on Apo-B mRNA (sequences 8786 and 6981) and their cognate siRNAswere transfected into mouse Hepa1-6 cells at different doses, byHaringsma et al., to generate dose response curves. The cells wereharvested 24 hours after the transfection and the target mRNA levelsdetermined. The 8786 siRNA had an IC₅₀ value of 15 pM vs. an IC₅₀ valueof about 1.2 nM for the ssRNAi while the 6981 siRNA had an IC₅₀ value of45 pM vs. an IC₅₀ value of about 0.9 nM for the ssRNAi. These valuesrespectively represent an 80× and a 20× greater potency for the siRNAover the cognate ssRNAi. The activity of all 4 of these compoundsplateaued at >90% target knockdown showing that ssRNAi can be as activeas a cognate siRNA but that it is much less potent than the siRNA.

Haringsma et al. also compared the activity, potency and duration ofeffect of the 8786 and 6981 ssRNAi compounds compared to their cognatesiRNA where the compounds were delivered to mouse liver cells in vivousing a protective lipid nanoparticle carrier. As for the in vitroexperiments, the siRNA passenger strands were unmodified except forsingle inverted abasic modifications at the 5′ and 3′-ends. When the twocognate compound types were compared at a dose of 3 mg/kg on day 3following the i.v. treatment of mice, the two ssRNAi compounds wereshown to produce a knockdown of the Apo-B mRNA target in the range of61-74% while the two siRNAs produced a knockdown in the range of 85-98%indicating that the ssRNAi compounds are less potent than the cognatesiRNA in mice at this dose. Note that giving the ssRNAi and siRNA at thesame drug weight means that the dose of ssRNAi will supply twice as manyguide strand to cells as the siRNA dose does.

A more striking difference between these two sets of cognate compoundsis that the ssRNAi compound in each set had a much shorter duration ofsuppressive activity against the target compared to the cognate siRNA.In these experiments all 4 compounds were administered at a dose of 6mg/kg and the target mRNA levels in mouse liver were determined on days2, 7 and 14. Throughout this time course administration of either of thesiRNA compounds resulted in a consistent level of target knock down inthe liver of about 95% while the two ssRNAi compounds showed a nearly a90%, 71-77% and no knockdown respectively at each of these time points.In addition, the siRNA but not the ssRNAi compounds resulted in acleavage of the target mRNA at the definitive site for siRNA inducedcleavage as determined by the 5′-RACE assay.

These data make it clear that the ssRNAi compounds have a lower potencyand a much shorter duration of effect on the target compared to thecognate siRNA. In addition, unlike siRNA, ssRNAi compounds fail toinduce cleavage of the target at the expected AGO-2 cleavage site (thesite in the target opposite nucleoside positions 10 and 11 of the guidestrand), but other considerations supported an RNAi mechanism for theeffect of these ssRNAi compounds.

In the absence of argonaute protein engagement, ssRNAi, are lessprotected from nuclease attack than the guide strand in a duplex withits passenger strand. For this reason the initial difference in activitybetween the two compositions used in the Haringsma et al. experiments onday 2 or 3 could simply reflect a greater level of degradation of thessRNAi compared to the siRNA guide strand in cells. But since the guidestrands in both compounds are the same, the differences subsequentlyseen in Apo-B mRNA levels and the different 5′RACE results cannot beexplained on the basis of differences in the guide strand sequence ormodifications. Instead these differences in effects on the targetbetween the ssRNAi and siRNA must be due to differences in the qualityof the interactions between the ssRNAi and siRNA guide strands and RISC,particularly with regard to the argonaute component of RISC that is indirect contact with the guide strand throughout all or nearly all of itslength.

Chorn et al. (RNA 18: 96-804, 2012) applied the same set ofmodifications as Haringsma et al., to ssRNAi 21-mer mimics of miR-124and miR-122. They transfected these compounds into HCT-116 cells andmeasured the levels of two mRNA targets each for the miRNAs beingmimicked.

Since the targeting code for these and most other miRNA guide strands isprimarily, if not exclusively, the seed sequence the rest of the guidestrand sequence can be largely altered at will. Taking advantage of thisChorn et al., also evaluated the activity of 88 ssRNAi mimics for whichthe bases (A, U, C or G) found in nucleoside positions 10-19 wererandomized. Several of the ssRNAi compounds with a randomly generatedpartial sequence were more active than an ssRNAi having the fullendogenous miR-124 guide strand sequence. A significant positivecorrelation was seen between the pyrimidine content of the randomizedsegment of the ssRNAi and its activity. Not every high pyrimidinecontent randomized sequence, however, was a top performer.

A randomized sequence from one of the best performing miR-124 mimics wasshown to be capable of significantly boosting the activity of an ssRNAimimic of miR-122 compared to an ssRNAi with the full miR-122 sequence.The IC₅₀ for the optimized miR-122 mimic was in the low single digitnanomolar range while the ssRNAi based on the full miR-122 sequenceexclusive of the endogenous overhang had no activity at doses lower than10 nM. Extrapolation of the dose response curve suggests that the IC₅₀for the latter ssRNAi was in the range of 100 nM.

Lima et al., (Cell 150: 883-94, 2012) generated newer 21-mer ssRNAicompounds with sufficient nuclease resistance to be systemicallyadministered to mice without a protective carrier. They also had enoughphosphorothioate linkages, although not an optimal number, to promotesufficient binding to plasma proteins to prevent the majority of thecompound from being rapidly eliminated from the body by the kidneysrather than being taken up by tissues from the general circulation. Themodifications used to promote nuclease resistance for the most potent ofthese ssRNAi compounds were as follows: (1) A 5′-VP-T_(moe) at the5′-end. T_(moe) is a thymidine with a 2′-methoxyethyl (2′-MOE)modification of the sugar. 5′-VP stands for 5′-(E)-vinylphosphonate amoiety that contains a double bond between nucleoside sugar carbons 5′and 6′ in a trans configuration. It is a 5′-phosphate analog with adouble bond that is expected to be resistant to phosphatases; (2)Nucleoside positions 20 and 21 were both adenosines with the 2′-MOEmodification (A_(moe)); (3) Nucleoside positions 2-19 were alternating2′-fluoro and 2′-O-methyl where a 2′-fluoro falls in position 14; and(4) Phosphorothioate linkages were used between consecutive nucleosidepositions 1-3 and 14-21. In nucleoside positions 3-14 phosphodiesterlinkages alternate with phosphorothioate bringing the total number ofphosphorothioates in the ssRNAi to 14. The synthesis methods forgenerating of oligos with 5′-VP include those described in WO2011/139699, WO 2011/139702, Lima et al., (Cell 150: 883-94, 2012) andPrakash et al., (Nucleic Acids Res 43: 2993-3011, 2015).

Lima et al. used electroporation to get varying doses of ssRNAi 21 orssRNAi 8 into mouse primary hepatocytes to determine the IC₅₀ for theirtarget, PTEN mRNA, 16 hours post electroporation. These ssRNAi compoundshad the same sequence and an identical pattern of modification as justdescribed except ssRNAi 21 had the 5′-VP-T_(moe) modification whilessRNAi 8 had a normal phosphate group conjugated to the 5′ carbon of theT_(moe) sugar rather than VP. The results showed IC₅₀ values of 1104 forssRNAi 21 and 1 μM for ssRNAi 8. This indicates that the compound with a5′ normal phosphate is about 10× more potent than the compound with the5′ phosphate analog in primary mouse hepatocytes.

Cells are known to vary widely in their susceptibility to transfectionso the very high IC₅₀ doses for both of these ssRNAi compounds could bedue to a poor susceptibility to transfection on the part of this celltype. This possibility is supported by the fact that the IC₅₀ for ssRNAi8 when Hela cells were used was 2±0.4 nM indicative of a 500× greaterpotency for this compound compared to its IC₅₀ based on primary mousehepatocytes.

Mice were treated with ssRNAi 8 at a total dose of 300 mg/kg and theeffect on mouse liver PTEN mRNA levels determined. (For this and theother experiments described below, the ssRNAi was delivered as a dividedtotal dose where 25 mg/kg was given twice a day s.c. for the requirednumber of days needed to reach the total dose.) There was no effect ofssRNAi 8 on the mRNA target. Recovery of the ssRNAi from the livershowed that the 5′-phosphate was no longer present on the ssRNAi afterbeing in liver cells for 6 hours while the rest of the strand wasintact. Lima et al. reasoned that the lack of activity against thetarget was due to this phosphate loss. This finding stands in markedcontrast to the finding of Haringsma et al. (2012) where their ssRNAicompound with a natural 5′-end phosphate was active in mouse liver overa period of several days.

Given the 10-fold lower potency of ssRNAi 21 compared to ssRNAi 8 inprimary hepatocytes additional ssRNAi sequences with the 5′-VP-T_(moe)modification were tested for their ability to suppress PTEN mRNA. Twowith a level of activity (IC₅₀ of 4 nM or 1 nM) similar to or the sameas ssRNAi 8 (IC₅₀ of 1 nM) using mouse primary hepatocytes were selectedfor further testing in mice. They were shown to be capable of causingabout a 55% knockdown of the target in mouse liver at either a totaldose of 300 mg/kg (ssRNAi 24) or a total dose of 100 mg/kg ssRNAi 27).The mice were sacrificed 48 hours after the last treatment.

In a subsequent experiment based on ssRNAi 27, the duration ofsuppression of PTEN mRNA in mouse liver was determined to be about 60%,30% and negligible respectively at 24 hours, day 10 and day 30 after thelast treatment using a 100 mg/kg total dose. In another experimentinvolving a 100 mg/kg total dose of ssRNAi 27, target levels at 48 hoursafter the last dose were determined to be 38% for kidney, 3% forskeletal muscle (quadricepts), 12% for lung and 5% for fat.

A dose response curve was generated for ssRNAi 27 using total doses of50, 100, 200 or 300 mg/kg and measuring the PTEN mRNA in mouse liver 48hours after the last dose. The respective percent reductions wereapproximately 25%, 50%, 65% and 65%.

ssRNAi 27 was also conjugated with the C16 carrier at nucleosideposition 8 to produce ssRNAi 29 and used to treat mice with a 100 mg/kgtotal dose. Forty-eight hours after the last dose the PTEN mRNA levelsin liver, kidney, skeletal muscle (quadricepts), lung and fat weredetermined and found to be approximately 50%, 25%, 20%, 30% and 35%respectively. Thus compared to ssRNAi 27, ssRNAi 29 was more active inskeletal muscle, lung and fat but less active in kidney while havingabout the same activity in liver.

Following the treatment of mice with either ssRNAi 24 or ssRNAi 27, itwas demonstrated using the 5′RACE assay that liver PTEN mRNA was cleavedat the expected site for an AGO-2 catalytic effect.

The Lima et al. (2012) data show that their ssRNAi compounds have modestactivity in liver and poor, or no activity in other organs/tissues, poorpotency and short duration of effect. Since they did not use a carrier,or used a carrier incapable of sufficiently promoting the uptake of ansiRNA, drug comparisons between their ssRNAi compounds and a cognatesiRNA were not possible. siRNA compounds delivered to the liver bycarrier, however, as well as antisense oligo drugs typically havesubstantially better activity, potency and duration of effect in livercompared to the Lima et al. ssRNAi compounds. Indeed, theseinvestigators disclosed in a recent paper that ssRNAi compounds,including theirs, require further development in order to becomecommercially viable as drugs (Prakash et al., Nucleic Acids Res 43:2993-3011, 2015).

SUMMARY OF THE INVENTION

In accordance with the present invention, methods, modifications andssRNAi compositions capable of providing RNAi activity in a wide rangeof organs/tissues/cell types against targets of interest in vitro and invivo are disclosed. The novel ssRNAi compounds of the present inventionare referred to herein as Accommodating Guide Strand RNAi (agsRNAi).Methods for producing agsRNAi rely on accommodating guide strand designs(AGSD) and the modifications involved are referred to as AGSDmodifications.

Three subtypes of agsRNAi fall within the scope of the presentinvention: ags-siRNA compounds having activity against selected mRNA orregulatory RNA target(s) excluding miRNA; ags-IMiRs having activityagainst selected miRNA or any selected simtron or mirtron targets; andags-MiRs mimics of selected endogenous miRNA or that have a noveltargeting code sequence which is capable of modulating expression and/orfunction of a novel set of targets by an miRNA mechanism. In the lattercase, the set of modulated targets are not engaged by the targetingcode(s) present in naturally occurring miRNAs. Ags-siRNA, ags-IMiR andags-MiR activities can be based on a catalytic or steric hindranceeffect.

Ags-MiRs that use the seed region as their targeting code can be furthersubdivided into those having a sequence that is closely or entirelybased on the sequence of the guide strand of the miRNA being mimicked(exclusive of the overhang) and those based on a modular designapproach. Ags-MiRs based on the modular approach have the same sequenceas the mimicked miRNA in positions 2-8 or 2-9 (so the seed sequence isretained) while the sequence ranging over positions 9 or 10 through 19is not the same as the mimicked endogenous miRNA.

Ags-siRNA non-coding regulatory RNA targets include but are not limitedto lncRNA, promoter associated RNA, enhancer RNA, snoRNA, piRNA, xiRNA,sdRNA, moRNA, MSY-RNA, tel-sRNA, crasiRNA and endogenous antisense RNA.Some ags-siRNA compounds can produce a change in expression and/ormodulate the function of genes by directly engaging DNA targets on thebasis of complementary base pairing including but not limited to one ormore entities controlling particular gene(s) and selected from the groupof promoters, enhancers or suppressors.

The fundamental problem with existing ssRNAi compounds is that thequality of their engagement with RISC, and argonaute protein inparticular, is very substantially compromised by the lack of a passengerstrand. The end result being reduced activity, potency and duration ofeffect on the target(s) compared to the cognate siRNA or miRNA.

AgsRNAi compounds are surprisingly superior to the ssRNAi compoundsknown in the art in one or more ways which include, without limitation,(1) Providing for a higher level of activity against the target(s) invitro and/or in subjects; (2) Exhibiting a greater potency against thetarget(s) in vitro and/or in subjects; (3) Producing a significantlylonger period of RNAi activity against the intended target(s) in vitroand/or in subjects; (4) More efficiently modulating the expressionand/or function of targets in low oligo uptake tissues/cell types insubjects without the use of a carrier; (5) Inclusion of a variety ofmodifications that provide features such as enhanced nucleaseresistance, enhanced plasma protein binding, enhanced effect on theintended target(s) and/or reduced off-target effects that can be made tossRNAi compounds without undermining the RNAi activity; and (6)Increasing the activity, potency and/or duration of activity obtained inthe absence of a 5′-phosphate or phosphate analog is not used.

Similar to conventional (double strand) siRNA and miRNA, the initialengagement of ss-RNAi and agsRNAi with the RNAi mechanism is consideredas a two-step process. The first step involves a reversible associationof the guide strand (in single strand form or in a duplex with apassenger strand) with the RISC loading complex (RLC). This step is notnecessarily essential but can increase the efficiency of the secondstep. Dicer is a key component of the RLC. Dicer binds both single anddouble strand RNA primarily through interactions between its PAZ domainand the 3′end half of the guide strand Some single strand RNA binds moretightly to Dicer than a cognate double strand compound. It is believedthat as part of the RLC, Dicer may, at least sometimes, play animportant role in the loading of the guide strand of an RNAi triggerinto the argonaute protein of RISC. This view is consistent with thedifferential guide strand regional binding preferences of Dicer (3′-endof the guide strand) and the argonaute (5′-end of the guide strand)proteins leaving aside any overhang or overhang precursor (Kini andWalton FEBS Lett 581: 5611-16, 2007; Lima et al., J Biol Chem 284:2535-48, 2009).

Guide strands including agsRNAi compounds can be divided into regionsbased on the particular domains of the argonaute protein that theyinteract with at least on an intermittent basis (Ma et al., Nature 429:318-322, 2004; Kini and Walton FEBS Lett 581: 5611-16, 2007; Lima etal., J Biol Chem 284: 26017-28, 2009; Schirle et al. Sci 346: 608-613,2014). These interactions involve non-covalent charge-chargeinteractions between particular moieties in the guide strand andparticular moieties in the associated domain of the argonaute protein.The relevant guide strand moieties include those associated with thesugar, sugar analog or sugar substitute (sugar) of a given nucleoside;those associated with the base associated with a given nucleoside; aswell as those associated with the linkages between the nucleosides.These guide strand/argonaute regions of potential interaction are thefollowing: (1) the 5′-end nucleosides in positions 1-2 are anchored tothe MID domain. The 5′ end nucleoside is conjugated to a 5′-phosphate orphosphate analog, if any, as desired. The phosphate or phosphate analoghas multiple attractive interactions with moieties in the MIDI domain.This 5′-end nucleoside is reoriented by conformational changes due toits interactions with the MIDI domain in a manner that makes itinaccessible to the target; (2) the nucleosides in positions 3-13 are inclose proximity to the PIWI domain and the linkages between thenucleosides in positions 3-6 interact with moieties in this domain tostabilize the association while the nucleosides in positions 6 and 7have more complex stabilizing interactions with the PIWI domain; (3)nucleosides that include positions 14-18 thread their way through anarrow channel between the PAZ and N domains. Positions 14-18 andpositions 14 and 16 in particular are more sterically restricted bythese domains in a manner that places greater constraints on themoieties projecting from these nucleosides such as any moiety in the 2′sugar position; and (4) nucleoside 19 plus any other nucleosides and/orother structural units that complete the 3′-end of the guide strandinteract with the PAZ domain. Any structural units in positions 20-23 inthe case of agsRNAi are referred to as overhang precursors because theycorrespond to any overhang in a siRNA or miRNA guide strand.

Broadly speaking, therefore, AGSD methods and the AGSD modificationsused to generate agsRNAi compounds can be more conveniently consideredon the basis of subdividing the compounds into three major regions. Eachof these regions includes both the nucleosides (or units whenreferencing the overhang precursor) and the intervening linkages,however, the nucleoside (or unit) position numbers are used to locatethe regions as follows: (1) Nucleoside position 1; (2) Nucleosidepositions 2-19; and (3) Any nucleosides or units in positions 20-23 thatconstitute any overhang precursor.

The superiority of agsRNAi over the ssRNAi known in the art relies, inpart, on the modifications made to each of these three regions whichcollectively give rise to increases in both the affinity of the compoundwith the Dicer component of the RLC, and with the argonaute component ofRISC as well as inreases the functional quality of the interaction withthe argonaute protein. In addition, the modifications made to each ofthese regions must not undermine the functioning of the RNAi mechanism.This primarily means the modifications made to any intended agsRNAicannot generate significant steric hindrance conflicts that interferewith the function of the RNAi mechanism, for example, by interferingwith the conformational changes in the argonaute protein that mustprogressively occur as the target is engaged.

The degree to which each of these regions of an intended agsRNAi isoptimized can affect the level of changes required in other regions, andindeed can reduce the degree to which the other regions need to beoptimized in order to achieve the same level of activity, potency and/orduration of effect against the intended target(s). For example, it isknown that a 5′-end phosphate substantially improves inhibitory functionof ss-RNAi compounds known in the art. Notably, the presence of a 5′-endphosphate on the guide strand of an siRNA or miRNA has no significanteffect on the functional abilities of these RNAi triggers. Thus, if therest of the ssRNAi could be made as efficient in engaging and directingthe RNAi mechanism as the guide strand that was delivered to the RNAimechanism as a double strand RNAi trigger then the requirement for a5′-phosphate on the ssRNAi would become irrelevant.

5′-end nucleoside modifications made to the nucleoside in position 1used in agsRNAi compounds are those known to the skilled artisan or canbe novel modifications provided by the present invention. The need fornovel modifications at this position is particularly pressing for ssRNAicompounds that are to be administered to subjects without a protectivecarrier and where the compound benefits functionally from having a 5′end phosphate or phosphate analog. Several modifications to this regionof an ssRNAi provided by the present invention are alternatives, forexample, to the 5′-VP-T_(moe) modification in nucleoside position 1known in the art. These novel modifications include those that involvethe use of the natural 5′-phosphate along with modifications to thenucleoside in position 1 and possibly position 2 as well thatsubstantially reduce the ability of phosphatases from removing thismoiety while also providing for protection from 5′-3′-exoribonucleaseattack. Alternative novel modifications provided by the presentinvention render the 5′-end nucleoside more susceptible tophosphorylation of its 5′ carbon by enzymes with this capability, suchas hClp1 RNA kinase, while at the same time providing for increased5′-3′-exoribonuclease resistance. The principal advantage of a number ofthese novel modifications is that by providing the means to have a5′-end phosphate present when the agsRNAi engages with the RNAimechanism, the functionality of the agsRNAi can be improved relative tothe same compound with the 5′-VP-T_(moe) modification known in the art.According to the present invention the 5′-VP moiety can also beconjugated certain nucleosides to produce novel nucleosides not known inthe art that result in significantly superior function of the agsRNAicompared to an identical agsRNAi with the 5′-VP-T_(moe) modification innucleoside position 1.

The AGSD modifications made to nucleoside positions 2-19 of an agsRNAicompound increase the probability that the modified nucleoside will haveits sugar in the C3′-endo conformation compared to the sugars(2′-fluoro, 2′-O-methyl and ribose) found in these positions in thessRNAi compounds known in the art. AGSD modifications include certainnucleoside sugars as well as certain nucleoside bases. The AGSDmodifications made to particular nucleosides also have the capacity toincrease the probability that the nucleosides immediately adjacent tothe modified nucleoside will also have their sugar in the C3′-endoconfirmation.

The sugars provided herein have variable degrees of flexibility thatreflect the ease with which they can undergo a conformational changeaway from the C3′-endo conformation. Sugars used in this region ofagsRNAi compounds that are not AGSD modifications (ribose, 2′-fluro and2′-O-methyl) are the most flexible. They are, therefore, the mostsusceptible to outside influences on their conformation. AGSD sugarmodifications are all less flexible than these non-AGSD sugars but canbe sub-categorized as being flexible, semi-flexible or rigid (Table 1).The less flexible they are the less susceptible they are to outsideinfluences changing their conformation away from the preferred C3′-endoconformation. A modification that would negatively impact the expressionof the 3′ endo conformation by contiguous nucleosides with more flexiblesugars is the presence of one or more 2′-deoxyribonucleosides in theagsRNAi strand. For this reason 2′-deoxyribonucleosides are generallynot used in positions 2-19 of agsRNAi compounds.2′-deoxyribonucleosides, however, can be used in linkage sites in anagsRNAi where the linkage joining them is a boranophosphate.

The rigid AGSD sugars are held in a C3′-endo confirmation by a shortchemical bridge inserted between the 2′ hydroxyl and 4 carbon positionsof a ribose. Consequently, their conformation cannot be affected byoutside influences, however, they are the most potent of the AGSD sugarsin terms of their ability to affect the sugar conformations ofcontiguous nucleosides. The semi-flexible AGSD sugars have a longerchemical bridge joining two points in the sugar while the flexible AGSDsugars do not have such chemical bridges.

AGSD modifications also include certain nucleoside bases that substitutefor U or C that can increase the likelihood that the nucleosidecontaining them and contiguous nucleosides will have their sugar in theC3′-endo confirmation, but the extent of this effect depends on thelevel of flexibility of the sugar found in the nucleoside in question.Again contiguous nucleosides with the most flexible sugars (ribose,2′-fluro or 2′-O-methyl) will experience the greatest level ofinfluence.

Nucleosides with purine bases (G or A) and a more flexible sugar areless likely to be in the C3′-endo confirmation compared to a nucleosidewith a purine (C or U) base with the same more flexible sugar. Theability of an AGSD modification to a given nucleoside to increase thelikelihood that the sugar in a contiguous nucleoside will be in theC3′-endo confirmation is affected by whether the contiguous nucleosidehas a purine base or a purine base as well as by the level offlexibility of its sugar.

Rules are provided herein that establish the minimum AGSD modificationsfor inclusion in any given agsRNAi sequence that will result in asignificant improvement in activity, potency and/or duration of effecton the intended target(s). Other rules establish the maximum proximitythat AGSD sugars can have with each other. Too many such modifications,particularly when they are in too close a proximity, can result insuboptimal function for the agsRNAi compound.

In addition, the specific AGSD modifications provided and theirpositioning avoid steric hindrance and other adverse interactionsbetween the agsRNAi and the RNAi mechanism that would significantlyinterfere with the ability of the agsRNAi to out perform an ssRNAilacking AGSD modifications in this region.

The general effect of the AGSD modifications to this region on theagsRNAi compound is to make its conformation significantly more like theconformation it would have if it were in a duplex with a complementarypassenger strand. The net functional effects of these modifications isthe production of agsRNAi compounds which demonstrate enhanced activity,potency and/or longer duration of effect on the agsRNAi target(s) overssRNAi known in the art.

Certain overhang precursors, which occur in one or more of positions20-23, are described by the present invention for use in agsRNAicompounds. These include those that are not found in association withssRNAi known in the art, but that have been used in siRNA. Thosepreviously not used with ssRNAi can provide a substantially greaterbenefit to ssRNAi compounds including agsRNAi than they can when presentin a cognate siRNA or cognate miRNA in terms of significantly increasedactivity, potency and/or duration of effect on the target.

In addition to the AGSD methods and AGSD modifications the currentinvention provides certain other improved capabilities for agsRNAicompounds that are of a more limited range. Increasing the bindingaffinity of the seed sequence for its targets, for example, ispositively correlated with the activity the seed sequence of an agsRNAicompound against some or all of its targets. In the case of ags-MiRsincreasing the activity could be a good outcome but for ags-siRNA andags-IMiRs reducing the activity of the seed sequence by reducing itsaffinity for its targets is more likely to be a positive outcome sinceit could reduce unintended off-target effects.

AGSD modification(s) to the seed sequence typically will increase thebinding affinity to its target(s), accordingly alterations in affinitymust be assessed when comparing the activity of an ags-MiR to an ssRNAiwith the same sequence. To make the comparison more accurate, themodifications to the seed sequence in both the ags-MiR and the ssRNAimimic must be the same in both compounds. In this way any differences inactivity, potency and/or duration of effect on the target(s) betweenthese two compounds must be due to differences or modifications whichoccur outside of the seed sequence.

The conclusion that the level of the affinity of a seed sequence for itstargets is generally positively correlated with the level of suppressionof its targets can be inferred from the results obtained by Ui-Tei'sgroup (Ui-Tei et al., Nucleic Acids Res 30: 7100-9, 2008) and laterfurther expanded by them (Hibio et al., Scientific Rep 2:996 pages 1-10,2012). Based on the Ui-Tei et al. (2008) data it is clear that affinitybetween a seed sequence and its mRNA target sequence is preferably above21.5 degrees centigrade for Tm and/or below a AG of −12 for those mRNAsthat are to be silenced and preferably below 15 degrees Tm and above −11AG for those that are not to be silenced. These figures set a usefulstandard of designing ags-MiR compounds with enhanced activity againsttheir targets and for designing ags-siRNA and ags-IMiR compounds withreduced off target effects due to the seed sequence.

Other nucleoside modifications are provided herein including2,6-diaminopurine (used in place of adenine) that can boost the bindingaffinity of the seed sequence for its targets (Table 2). Thismodification can also prevent the adenosine to inosine editing inags-MiR compounds that can sometimes occur to adenosines in the seedregion of naturally occurring miRNAs. The effect of such editing hasbeen shown to substantially alter the mRNA target profile of the alteredmiRNA (Kume et al., Nucleic Acids Res 42: 10050-60, 2014).

The duration of the effect of an agsRNAi on its target(s) in cells inthe body, in part, is a function of how stable it is in the cells.Hence, methods that reduce the rate of turnover can be used to increasethe duration of its effect. The clearance of single strand therapeuticoligos from cells in the body follows cleavage of the oligo into two ormore parts by intracellular nucleases, most often by endonucleases. Oncecleaved the oligo fragments escape from the cell and most of thefragments end up in the urine.

There are important species and organ/tissue/cell type differences inthe rate of oligo clearance from particular cells in the body due todifferences in the rate of cleavage for the same oligo. Cleavage ratedifferences can be quite large and are typically measured in days orweeks (greater than 5 fold difference in some comparisons). For example,in general the livers of numerous species of subjects cleave theseoligos more rapidly than many other organ/tissue/cell types in the samespecies. As a further example, the organs, tissues and cells in micetypically are more active in cleaving oligos than the correspondingorgans, tissues and cells in other species used in drug developmentincluding rats and monkeys (Geary et al., Drug Metab Disposition 31:1419-28, 2003).

Similarly, the rate of clearance of agsRNAi compounds from a subject isboth species and organ/tissue/cell type dependent. Thus, it is importantto consider in which organ/tissue/cell type(s) and in what species is itdesirable to have a prolonged effect on the target(s) relative to otherorgan/tissue/cell types in the subject. AgsRNAi cleavage in cells can bequantified and the specific linkage sites and the rate at which they arecleaved can be determined using liquid-chromatography-coupled massspectroscopy (Lima et al., Cell 150: 883-94, 2012).

When an agsRNAi is degraded in a particular organ/tissue/cell type morequickly than is desired relative to other organ/tissue/cell types in thesame subject, there are at least two possible solutions: (1) theoffending cleavage sites and the rate of cleavage of the agsRNAi can bedetermined for particular organ/tissue/cell types. Using the guidanceprovided herein, it is possible to increase the nuclease resistance ofthe cleaved site(s) without unduly affecting the desired level of RNAiactivity; and (2) an appropriate passenger strand complementary to theagsRNAi can be administered to the subject.

An appropriate passenger strand is one that protects the agsRNAi notengaged by RISC from intracellular nuclease attack until the agsRNAi isloaded into an argonaute protein. In addition, an appropriate passengerstrand is one that is designed to facilitate the loading of the guidestrand, in this case an agsRNAi, into RISC in accordance with theprinciples known in the art, for example: (1) the thermodynamicasymmetry rule that involves the terminal 4 nucleosides in each strandthat are duplexed with the other strand must be applied. Specifically,the duplexed end that includes the 5′-end of the passenger strand musthave a higher binding affinity with the agsRNAi strand compared to theopposite duplexed end that includes the 5′-end of the agsRNAi (Khvorovaet al., Cell 115: 209-16, 2003; Schwarz Cell 115: 199-208, 2003); and(2) for agsRNAi in general the central region of the passenger strandcomprising nucleosides 8-11 counting from the 5-end preferably has anucleoside selected from the group consisting of a single mismatch withthe agsRNAi, an abasic nucleoside, an UNA containing nucleoside, anucleoside with a 2,4 difluorotoyl base and a nucleoside with a5-nitroindole base (Liu et al., Science 305: 1437-41, 2004; Meister etal., Mol Cell 15: 185-97, 2004; Yoda et al., Nature Struct Mol Biol 17:17-23, 2010; WO 2010/011895). For ags-siRNA and ags-IMiRs, however, thepassenger strand linkage site defined by nucleosides in positions 9 and10 (opposite nucleoside positions 10 and 11 in the ags-siRNA orags-IMIR) optionally has a phosphodiester linkage and these nucleosidesindependently have a ribose and/or 2′-fluoro sugar.

If the passenger strand is not delivered to cells in a subject by meansof a protective carrier then it must be sufficiently modified to resistdegradation by extracellular nucleases between the time it isadministered and the time that it enters cells. Further, suchmodifications cannot undermine the intended RNAi activity. Consequently,it is preferable that the passenger strand is designed as a seqRNAipassenger strand in accordance with the methods and compositionsdisclosed in WO 2012/145729). Alternatively, the passenger strand isdesigned using compositions and other methods known in the art forproducing a passenger strand, for example those found in the McSwiggenpatents and filings that cover a range of possible passenger strandmodifications and modification placements in the strand (WO 03/070918;WO 03/074654; WO 2005/019453; and WO 2007/022369 along with the relatedfilings and patents). The McSwiggen passenger strands, however, have notbeen designed for single strand administration to a subject without aprotective carrier. As a result, a protective carrier and/or addednuclease resistant linkages added using one of the patterns provided forherein.

A carrier could be used to target the passenger strand to the specificorgan/tissue/cell type(s) where the agsRNAi is to be protected. Forexample, an enveloping nanoparticle carrier known in the art, such asthe Tekmira SNALP carrier (WO 2009/086558; WO 2010/042877), or one thecarriers that incorporate a ligand(s) for the asialoglycoproteinreceptor (such as ones based on N-acetylglucosamine) could be conjugatedto the passenger strand (Rozema et al., Proc Natl Acad Sci (USA) 104:12982-87, 2007; Nair et al. J Am Chem Soc 136: 16958-61, 2014; WO2008/131419; WO 2011/104169). These carrier examples are known toefficiently deliver oligo drugs to the liver in a number of speciesincluding humans.

One or more of the following sets of conditions can document variousaspects of the surprisingly better performance of a particular agsRNAiof the present invention over a corresponding ssRNAi designed usingmethods and modifications known in the art:

A single strand modified oligoribonucleotide agsRNAi composition(ags-siRNA, ags-IMiR or ags-MiR) for modulating the expression and/orfunction of at least one target nucleic acid sequence expressed bysubject cells;

-   -   wherein said subject cells are of the same type and are selected        from the group consisting of a particular cell line; a        representative sampling of a particular organ, gland or        neoplastic growth; an enriched sample of parenchymal cells from        a particular organ, gland or neoplastic growth; a particular        type of epithelial tissue including simple, stratified,        pseudostratified and transitional; a particular type of        connective tissue where the general types are loose and dense        forms as well as more specialized types that include reticular,        adipose, blood and lymphoid connective tissues; a particular        type of nervous tissue subdivided by location (such as brain,        spinal cord, ganglion, and nerve) and/or by cell type, i.e.,        neuronal or glial; and a particular type of muscle tissue where        the types are skeletal, cardiac and smooth; and wherein said        composition comprises:    -   I) A nucleoside in position 1 and an associated linkage with the        nucleoside in position 2 where the modifications to these        structure are provided in the section entitled “Designing        AgsRNAi Compounds: 5′-End Modifications”; and    -   II) 19 nucleosides        -   a) where the modifications in positions 2-19 provide for            basic nuclease resistance where the various sets of basic            nuclease resistance designs are provided in the section            entitled “Designing AgsRNAi Compounds: Providing Basic            Nuclease Resistance”; and        -   b) where there are at least 4 AGSD modifications where AGSD            and AGSD modifications are provided in the section entitled            “Designing AgsRNAi Compounds: Nucleoside Positions 2-19”;            and    -   III) optionally has 1-4 overhang precursor units where the        design of overhang precursors are provided in the section        entitled “Designing AgsRNAi Compounds: Overhang Precursors”; and    -   IV) a region of complementary base pairing with the target        nucleic acid(s) (referred to as the targeting code) that        -   a) for an ags-MiR is either 6 or 7 consecutive nucleotides            in length beginning at position 2 or is 11 or 12 consecutive            nucleosides in length beginning at position 4 or 5 although            optionally position 8 or 9 can have a mismatch with the            target; or        -   b) for an ags-siRNA or ags-IMiR is at least 15 consecutive            nucleosides in length beginning at position 2 and extending            through position 16 although optionally position 8 or 9 can            have a mismatch with the target; and

wherein

-   -   said modified oligoribonucleotide agsRNAi strand meets one or        more of the following sets of criteria (A-J) for demonstrating        at least one of the advantages of an agsRNAi compound over        ssRNAi compounds known in the art; and:    -   A) the agsRNAi composition is an ags-siRNA or ags-IMiR and        provides a maximal plateau level of activity in a dose response        curve against the target in said cells that constitutes at least        a 50, 60, 70, 80 or 90% change in expression and/or function of        the target and said level of change in activity is equal to or        greater than 20, 30 or 40 percentage points greater (e.g., for        greater than 20 percentage points the ssRNAi activity would be        less than 30, less than 40, less than 50, less than 60 or less        than 70% respectively) than the maximal level of activity        obtained using an ssRNAi of the same sequence, same 5′-phosphate        or 5′-phosphate analog, if any, and lacking the AGSD        modifications found in the agsRNAi as well as administered using        the same dosage regimen under one or more of the following        conditions of administration of the two compounds to be        compared:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using a method selected from the            group transfection, electroporation and gymnosis; or        -   b) to a subject where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier; or        -   c) to a subject where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier; or    -   B) the agsRNAi composition is an ags-MiR and provides a maximal        plateau level of activity in a dose response curve(s) against at        least 1, 2, 3 or 4 targets in said cells where each maximal        plateau level of activity constitutes at least a 20, 30, 50, 60,        or 70% change in expression and/or function per target and said        level of change in activity is equal to or greater than 20, 30        or 40 percentage points greater (e.g., for greater than 20        percentage points the ssRNAi activity would be 0 or less than        10, less than 30, less than 40 or less than 50% respectively)        than the maximal level of activity obtained using an ssRNAi with        the following properties in common with the ags-MiR: i) the same        sequence; (2) the same 5′-phosphate or 5′-phosphate analog, if        any; and (3) the same modifications in the seed sequence.    -   wherein both the ags-MiR and the ssRNAi are administered using        the same dosage regimen under one or more of the following        conditions:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using a method selected from the            group transfection, electroporation and gymnosis; or        -   b) to a subject where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier; or        -   c) to a subject where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier; or    -   C) the agsRNAi composition is an ags-siRNA or ags-IMiR that        provides an IC₅₀ or EC₅₀ against the target in said cells where        the amount of the agsRNAi compound is at least 2, 4, 8, 16 or 32        fold lower than the amount of an ssRNAi of the same sequence,        same 5′-phosphate or 5′-phosphate analog, if any, but lacking        AGSD modifications as well as administered using the same dosage        regimen needed to achieve an IC₅₀ or EC₅₀ against the target in        said cells under one or more of the following conditions of        administration of the two compounds to be compared:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using a method selected from the            group transfection, electroporation and gymnosis and the            IC₅₀ or EC₅₀ is measured as a molarity; or        -   b) to a subject where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier and the IC₅₀ or EC₅₀ is measured as mg/kg            administered to the subject; or        -   c) to a subject where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier and the IC₅₀ or EC₅₀ is measured as mg/kg            administered to the subject; or    -   D) the agsRNAi composition is an ags-MiR that provides an IC₅₀        or EC₅₀ against at least 1, 2, 3 or 4 target(s) in said cells        where the amount of the agsRNAi compound is at least 2, 4, 8, 16        or 32 fold lower than the amount of an ssRNAi with the following        properties in common with the ags-MiR: i) the same sequence; (2)        the same 5′-phosphate or 5′-phosphate analog, if any; and (3)        the same modifications in the seed sequence. The ssRNAi,        however, lacks any other AGSD modifications present in the        ags-MiR.    -   wherein both the ags-MiR and the ssRNAi are administered using        the same dosage regimen needed to achieve an IC₅₀ or EC₅₀        against the target in said cells under one or more of the        following conditions of administration of the two compounds to        be compared:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using a method selected from the            group transfection, electroporation and gymnosis and the            IC₅₀ or EC₅₀ is measured as a molarity; or        -   b) to a subject where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier and the IC₅₀ or EC₅₀ is measured as mg/kg            administered to the subject; or        -   c) to a subject where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier and the IC₅₀ or EC₅₀ is measured as mg/kg            administered to the subject; or    -   E) the agsRNAi composition is an ags-siRNA or ags-IMiR and        provides at least a 50, 60, 70, 80 or 90% change in expression        and/or function of the target in said cells at a time point        after the last treatment where at that time point the level of        change in expression and/or function of the target in said cells        is equal to or greater than 40, 50, 60, 70 or 80 percentage        points higher (e.g., for greater than 50 percentage points the        ssRNAi activity would be 0, 0, less than 10, less than 20 or        less than 30% respectively) than the level obtained at that time        point using an ssRNAi of the same sequence, same 5′-phosphate or        5′-phosphate analog, if any, and lacking the AGSD modifications        as well as administered using the same dosage regimen under one        or more of the following conditions of administration of the two        compounds to be compared:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using a method selected from the            group transfection, electroporation and gymnosis; or        -   b) to a subject where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier; or        -   c) to a subject where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier; or    -   F) the agsRNAi composition is an ags-MiR and provides at least a        20, 30, 50, 60, or 70% change in expression and/or function per        target for at least 1, 2, 3 or 4 targets in said cells at a time        point after the last treatment where the level of change in        expression and/or function of the target in said cells is equal        to or greater than 20, 30, 40, 50, 60 or 70 percentage points        higher (e.g., for greater than 30 percentage points the ssRNAi        activity would be 0, 0, less than 20, less than 30 or less than        40% respectively) than the level obtained at that time point        using an ssRNAi with the following properties in common with the        ags-MiR: i) the same sequence; (2) the same 5′-phosphate or        5′-phosphate analog, if any; and (3) the same modifications in        the seed sequence. The ssRNAi, however, lacks any other AGSD        modifications present in the ags-MiR.    -   wherein both the ags-MiR and the ssRNAi are administered using        the same dosage regimen under one or more of the following        conditions:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using a method selected from the            group transfection, electroporation and gymnosis; or        -   b) to a subject where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier; or        -   c) to a subject where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier; or    -   G) the agsRNAi composition is an ags-siRNA or ags-IMiR and is        systemically administered to a subject without an enveloping        protective carrier that increases the amount of an oligo taken        up by said cells    -   wherein        -   a) the agsRNAi provides at least a 50, 60, 70, 80 or 90%            change in expression and/or function of the target in said            cells and said cells are not a liver organ sample or an            enriched hepatocyte sample; and        -   b) the ratio of the weight in grams of the intact agsRNAi in            said cells divided by a unit weight of said cells expressed            in grams compared to the weight in grams of the intact            agsRNAi in said sample of the liver organ or enriched            hepatocyte population from the liver organ sample divided by            a unit weight of sample of the liver organ or enriched            hepatocyte population from the liver organ sample expressed            in grams is less than 0.3, less than 0.2, or less than 0.1            (e.g., if the agsRNAi weight per gram of lung sample is            43±10 and the agsRNAi weight per gram of liver sample is            950±129 then the ratio of lung to liver sample is 0.05 which            is less than 0.1); and    -   wherein under the same conditions the level of change in        expression and/or function of the target in said cells treated        with said agsRNAi is equal to or greater than 40, 50, 60, 70 or        80 percentage points higher (e.g., for greater than 50        percentage points the ssRNAi activity would be 0, less than 10,        less than 20, less than 30, less than 40% respectively) than the        level obtained using an ssRNAi of the same sequence, same        5′-phosphate or 5′-phosphate analog, if any, and lacking AGSD        modifications without an enveloping protective carrier that        increases the amount of an oligo taken up by said cells; or    -   H) the agsRNAi composition is an ags-MiR and is systemically        administered to a subject without an enveloping protective        carrier that increases the amount of an oligo taken up by said        cells    -   wherein        -   a) the ags-MiR provides at least a 20, 30, 50, 60, or 70%            change in expression and/or function against at least 1, 2,            3 or 4 targets in said cells and said cells are not a liver            organ sample or an enriched hepatocyte sample; and        -   b) the ratio of the weight in grams of the intact ags-MiR in            said cells divided by a unit weight of said cells expressed            in grams compared to the weight in grams of the intact            ags-MiR in said sample of the liver organ or enriched            hepatocyte population from the liver organ sample divided by            a unit weight of sample of the liver organ or enriched            hepatocyte population from the liver organ sample expressed            in grams is less than 0.3, less than 0.2, or less than 0.1            (e.g., if the ags-MiR weight per gram of lung sample is            43±10 and the ags-MiR weight per gram of liver sample is            950±129 then the ratio of lung to liver sample is 0.05 which            is less than 0.1); and    -   wherein    -   under the same conditions the level of change in expression        and/or function of the target in said cells treated with ags-MiR        is equal to or greater than 20, 30, or 40 percentage points        higher (e.g., for greater than 20 percentage points the ssRNAi        activity would be 0, less than 10, less than 20, or 40%        respectively) than the level obtained using an ssRNAi with the        following properties in common with the ags-MiR: i) the same        sequence; (2) the same 5′-phosphate or 5′-phosphate analog, if        any; and (3) the same modifications in the seed sequence. The        ssRNAi, however, lacks any other AGSD modifications present in        the ags-MiR and administered without an enveloping protective        carrier that increases the amount of an oligo taken up by said        cells; or    -   I) A kit comprising a first composition that is an agsRNAi where        it is an ags-siRNA or an ags-IMiR and a second composition        comprising a passenger strand that is complementary to the first        composition wherein the compositions are separately administered        to said cells such that the first or second composition is taken        up by the cells prior to the administration of the other        composition to the cells;        -   wherein        -   a) a duplex of first and second compositions functions as an            siRNA        -   b) the passenger strand promotes the loading of the agsRNAi            into RISC in preferences to itself; and        -   c) the first and second compositions are administered to            cells grow in vitro or in a subject according to one of the            following sets of circumstances:            -   i) mammalian cells grown in vitro where mammalian cells                are selected from the group consisting of a cell line,                primary cells and primary parenchymal cells and where                both compounds are delivered to said cells using a                method selected from the group transfection,                electroporation and gymnosis; or            -   ii) a subject where both of the compounds are delivered                to said cells with an enveloping protective carrier; or            -   iii) a subject where one of the compounds is delivered                to said cells with an enveloping protective carrier; or            -   iv) a subject where the both compounds are delivered to                said cells with a carrier other than an enveloping                protective carrier and the passenger strand is modified                to be sufficiently nuclease resistant for systemic                administration to the subject; or            -   v) a subject where the one compounds is delivered to                said cells with a carrier other than an enveloping                protective carrier; or            -   vi) a subject where neither of the compounds are                delivered to said cells by a carrier; and    -   wherein    -   at a certain time point after the last treatment the level of        change in expression and/or function of the target in said cells        is equal to or greater than 40, 50, 60, 70 or 80 percentage        points higher than the level obtained at that time point using        the agsRNAi in the absence of the passenger strand; or    -   J) the agsRNAi is an ags-MiR and provides at least a 20, 30, 50,        60, or 70% change in expression and/or function per target for        at least 1, 2, 3 or 4 targets in said cells at a time point        after the last treatment where the level of change in expression        and/or function of the target in said cells is equal to or        greater than 20, 30, 40, 50, 60 or 70 percentage points higher        (e.g., for greater than 30 percentage points the ssRNAi activity        would be 0, 0, less than 20, less than 30 or less than 40%        respectively) than the level obtained at that time point using        an ssRNAi with the following properties in common with the        ags-MiR: i) the same sequence; (2) the same 5′-phosphate or        5′-phosphate analog, if any; and (3) the same modifications in        the seed sequence. The ssRNAi, however, lacks any other AGSD        modifications present in the ags-MiR.    -   wherein both the ags-MiR and the ssRNAi are administered using        the same dosage regimen under one or more of the following        conditions:        -   a) to a mammalian cell line or primary mammalian parenchymal            cells grown in vitro where the compounds to be compared are            delivered to said cells using transfection; or        -   b) to subjects where the compounds to be compared are            delivered to said cells with an enveloping protective            carrier; or        -   c) to subjects where the compounds to be compared are            delivered to said cells without an enveloping protective            carrier.

The miRNA sequences and nomenclature used herein are taken from themiRBase (www.mirbase.org). The nomenclature has been described inGriffiths-Jones et al., Nucleic Acids Res 34: D140-D144, 2006. In brief,numbers that immediately follow the designation miR-, for example,miR-29, designate particular miRNAs. The specific designation is appliedto the corresponding miRNAs across various species. Letters, for examplein miR-34a and miR-34b, distinguish particular miRNAs differing in onlyone or two nucleoside positions in the mature miRNA (guide or antisensestrand that loads into RISC). Numbers following a second dash, forexample in miR-24-1 and miR-24-2, distinguish distinct loci that giverise to identical mature miRNAs. Multiple miRNAs family members thatdiffer in only one or two nucleoside positions in the mature mRNA fromsome other family member(s) and come from distinct hairpin loci haveboth letters and additional numbers following the letters, for example,miR-29b-1 and miR-29b-2. Finally, in some instances two different maturemiRNA sequences are excised from the same hairpin precursor where onecomes from the 5′ arm and the other from the 3′ arm. These aredesignated -5p and -3p respectively, for example, miR-17-5p andmiR-17-3p

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: CENA

FIG. 2: HM

FIG. 3: UNA (Unlocked Nucleic Acid)

FIG. 4: ANA

FIG. 5: EA

FIG. 6: 6A: HNA; 6B: 3′-FHNA

FIG. 7: AENA

FIG. 8: CRN (Confomationally Restricted Nucleoside); 8A: R monomer; 8B:Q monomer

FIG. 9: LNA (Locked Nucleic Acid); 9A; classic LNA and α-L-LNA; 9B:Thio-LNA and Amino LNA

FIG. 10: Five Examples of Abasic Nucleosides

FIG. 11: CeNA

FIG. 12: 5′ Carbon: Site for 5′-End Terminal Modifications

FIG. 13A: 2′-O-Methoxyethyl (2′-MOE) Modification of a Ribonucleoside;13B: Ethyl Bicyclic Nucleic Acid (cEt)

FIG. 14: C10 (TC10) and C16 (TC16) Conjugation to a NucleosideIllustrated with a Thymine Containing Nucleoside

FIG. 15: Structure for 5′-(E)-vinyl-phosphonate Conjugated to a ThymineContaining 2′-O-MOE Nucleoside (5′-VP-T)\

FIGS. 16A-E. Linkages useful in the compounds of the invention. FIG.16A: phosphodiester. FIG. 16B: phosphorothioate. FIG. 16C: N3phosphoramidate; FIG. 16D: amide linkage. FIG. 16E: boranophosphatelinkage.

FIG. 17: Synthesis of 3′-H-Boranophosphonate Monomers 3a-e. summarizesthe synthesis of the 2′-deoxyribonucleoside 3′-H-boranophosphonatemonomers 3a-d and locked nucleic acid (LNA) thymidine3′-H-boranophosphonate monomer 3e. 2′-Deoxythymidine monomer 3a wasobtained in 95% from the thymidine derivative bearing the 3′-OH 1a andpyridinium H-boranophosphonate 2. 2′-Deoxyadenosine, cytosine,guanosine, and LNA thymidine monomers 3b-e were synthesized by themethod for the synthesis of 3a with some modifications.

FIG. 18: Solid-Phase Synthesis of PBX-ODNs. Scheme 2 shows the synthesisof P-boronated oligodeoxyribonucleotides bearing oxygen, sulfur, or2-morpholinoethylamino as the substituent X on the phosphorus atoms(PBX-ODNs) via H-boranophosphonate oligodeoxyribonucleotides (PBH-ODNs).The monomers 3a-e were condensed with the 5′-OH of nucleosides or oligoson a controlled-pore glass (CPG) in the presence of1,3-dimethyl-2-(3-nitro-1,2,4-triazol-1-yl)-2-pyrrolidin-1-yl-1,3,2-diazaphospholidiniumhexafluorophosphate (MNTP)19 and 2,6-lutidine, and the 5′-end wasdeprotected by 3% dichloroacetic acid (DCA). Released dimethoxytrityl(DMTr) cations were reduced by Et3SiH, because they would otherwisecause side reactions with the internucleotidic BH3 groups. The PBH-ODNchains were elongated by this cycle, and the modification of thephosphorus atoms and subsequent deprotection afforded PBX-ODNs.

DETAILED DESCRIPTION OF THE INVENTION A. Overview of Prior Art

Plasterk's group provided the first publication describing ssRNAi inJanuary 2002 (Tijsterman et al., Science 295: 694-97, 2002). It appearedbefore the priority date for the first ssRNAi patent filing in July 2002(WO 2004/007718) by Tuschl and his colleagues. The Plasterk ssRNAicompounds had a 5′-end phosphate group. Naturally occurring siRNA andmiRNA have a 5′-end phosphate on each strand, but it has been shown thatdouble strand RNAi drugs do not require this structure to be active.ssRNAi compounds known in the art when tested in tissue culture,however, typically have higher activity if they are manufactured with a5′-end phosphate group or a suitable analog. The issued Tuschl ssRNAipatent (U.S. Pat. No. 8,101,348) based on the July 2002 PCT filingincludes a number of different 5′-end phosphate analogs, but the methodof use claim involving these analogs is restricted to silencing targetsin tissue culture.

Plasterk's initial publication on ssRNAi and the initial patent filing(WO 2004/007718) on ssRNAi was soon followed by a number of other earlypublications and another patent filing (Martinez et al., Cell 110: 563,2002; Schwarz et al., Mol Cell 10: 537, 2002; Holen et al., NucleicAcids Res 31: 2401, 2003; WO 2004/063375).

The initial burst of activity focusing on ssRNAi that began in 2002quickly subsided. Likely reasons include the generally poor tolerance ofssRNAi to chemical modifications that could impart sufficient nucleaseresistance to permit its use in subjects, even if used with a protectivecarrier.

In the first of two outliers Hall et al., (2004) showed that theincorporation of boranophosphate linkages along with phosphodiesterlinkages into the guide strands of siRNA compounds could frequentlysubstantially increase their potency. The main exception was the findingthat using a 5′-(α-P-borano) triphosphate to insert a nucleoside in morethan one of the 5 nucleosides in positions 8-12 counting from the 5′-endof the guide strand had an inhibitory effect on potency. The authorssuggested this negative effect might be due to the fact that this regionincludes positions 10 and 11 that are opposite the target cleavage sitefor AGO-2. Making boranophosphate linkage modifications to the passengerstrand had little effect on potency. These ssRNAi compounds weresynthesized using a DNA template, 5′-(α-P-borano) triphosphates and T7RNA polymerase. Given this approach the boranophosphate linkagesnecessarily were associated with nucleosides having one or more of aparticular type of base. There were no other modifications in thesessRNAi compounds and no modifications in the cognate siRNA compoundsused as a comparator. The boranophosphate linkage provided substantialadded nuclease resistance for the sites in an RNA strand where they arefound but the ssRNAi compounds studied were not sufficiently stabilizedfor use in subjects. RNase A treatment of the modified and unmodifiedssRNAi strands were both degraded at the same rate.

The guide strand from the most potent siRNA in the Hall et al. (2004)was evaluated in the studies published in 2006 by this group. In both ofthese papers, the target was enhanced green fluorescence protein (EGFP)under the control of an inducible promoter and expressed in Hela cells.The RNAi triggers were transfected into the Hela cells. The ssRNAi andcognate siRNA compounds without boranophosphate linkages that weretested were 21-mers with UU overhangs.

Remarkably the boranophosphate modified ssRNAi was found to be about8-fold more potent than the cognate unmodified siRNA, IC₅₀=about 1 nmvs. IC₅₀=about 8 nm respectively. The peak activity was also greater forthe ssRNAi being about 99% target suppression vs. 70% respectively. Theeffect of the ssRNAi and the cognate siRNA were both shown to be due toan AGO-2 mediated cleavage of EGFP mRNA. All the nucleosides in thisssRNAi with cytosine (total of 6) or adenine (total of 2) were linked tothe adjacent nucleoside by a boranophosphate linkage (total of 8boranophosphate linkages). Other patterns of modification wheredifferent nucleoside base type were associated with the boranophosphatelinkage also boosted activity of this ssRNAi relative to the cognatesiRNA. This occurred as long as the pattern of boranophosphatemodification did not cause the majority of the nucleosides in positions8-12 to be linked to a contiguous nucleoside by a boranophosphatelinkage. By evaluating a second ssRNAi sequence that had a differentratio of nucleosides defined by their bases it was shown that theadverse effect of the modified linkage being associated with anucleoside in positions 8-12 was not dependent on the base but rather onthe number of boranophosphate linkages in this region.

Taken together Hall et al. (2004 and 2006) show that boranophosphatemixed with phosphodiester linkages frequently can substantially boostthe effectiveness of guide strands against their targets in both thesiRNA and ssRNAi formats. These studies, however, to not provide theinformation necessary for determining the optimal placement of theboranophosphate linkages in these guide strands since it was notpossible to dissociate this linkage from the base type of its associatednucleoside. The nucleoside positions associated with the boranophosphatelinkage in the most active ssRNAi, however, were 4, 5, 6, 7, 11, 14, 15and 19. More recently methods for chemically incorporatingboranophosphate linkages into oligonucleotides have been developed.Synthetic schemes are provided in FIGS. 17 and 18. Also see Uehara etal., J Organic Chem 79: 3465-72, 2014.

As discussed in more detail in the “Background of the Invention,” in2012, interest in ssRNAi was again stimulated. Two publications eachfrom Isis Pharmaceuticals and Sirna Therapeutics (owned by Merck)demonstrated for the first time that ssRNAi could routinely be developedwith the capacity to substantially inhibit messenger RNA targets ofchoice in the livers or brains of mice. One Sirna study also dealt withssRNAi compounds with miRNA mimic activity. The three published patentapplications associated with these publications have 2010 priority dates(WO 2011/139699, WO 2011/139702 and WO 2012/027206). Isis filed thefirst two of these and Merck filed the third. The single Merck patentfiling based on the Sirna data (WO 2012/027206) disclosed in the two2012 papers is limited to compounds comprising non-nucleic acid spacers,which is an optional feature of their ssRNAi compounds. These spacersare included to facilitate attachment if various structures such asfluorescent tags. The Merck Sirna filing (2010 priority date andpublished March 2012) did not disclose ssRNAi compounds with miRNA mimicactivity.

Originally it was assumed that the 2′-fluoro modification, which isextensively used in the newer ssRNAi, promotes a higher binding affinitybetween it and a complementary RNA or DNA strand as a result of aproposed 2′-fluoro-dependent conformational preorganization that favorsthe A-type helical conformation when a duplex is formed. Recent detailedconformational studies, however, have shown that there is littledifference between unmodified single stranded RNA in this regard andsingle stranded 2′-fluoro RNA (Pallan et al., Nucleic Acids Res 39:3482, 2011). Instead the effects of this modification on duplexstability have been found to be due to enthalpy. Duplexes involving2′-fluoro RNA strand or strands are less hydrated than unmodified RNAduplexes.

B. Definitions and Defined Phrases

The following definitions and defined phrases are provided to facilitatean understanding of the invention.

“2′-fluoro” refers to a nucleoside modification where the fluorine hasthe same position and stereochemical orientation as the 2′-hydroxyl inβ-D-ribofuranose. In instances where the fluorine has the sameorientation as the 2′-hydroxyl in β-D-arabinofuranose, the associatednucleoside is referred to as FANA or 2′-deoxy-2′-fluoro-arabinonucleicacid.

“2′-O-methyl” refers to a 2′-O-methyl ribose modification.

“2′-MOE” or “MOE” refers to a 2′-O-methyoxyethyl ribose modification asillustrated in FIG. 12A.

“3′-supplementary or 3′-compensatory sites” refers to sites in somemiRNA guide strands down-stream of the seed sequence that arecomplementary to the target sequence and contribute to target selectionparticularly when the seed sequence has a weak match with the target.

“3′UTR” is an abbreviation for the 3′ untranslated region of an mRNA.

“4'S-FANA” refers to 2′-deoxy-2′-fluoro-4′-thioarabinonucleic acid(Watts et al., Nucleic Acids Res 35: 1441-51, 2007)

“5′-end module” refers to the 5′-end terminal 8 or 9 nucleosides foundin an ags-MiR or ssRNAi with miRNA-like activity where the compound isconstructed using the modular approach.

“5′-phosphate” or “5′-phosphate analog” refers to a phosphate orphosphate analog conjugated to the 5′ carbon of the 5′-end nucleosidesugar of an RNAi trigger.

“5′-to-3′ mRNA decay pathway” refers to a naturally occurring pathwayfor degrading mRNA that is initiated by the removal of the poly(A) tailby deadenylases. This is followed by removal of the 5′-cap andsubsequent 5′ to 3′ degradation of the rest of the mRNA.

“Abasic nucleoside” refers to any of a number of structures thattypically have a normal or modified nucleoside sugar and can be linkedto other nucleosides. The position normally occupied by the base hassome chemical moiety, such as a methylene group, that is not an isostereof any naturally occurring base found in nucleic acids and that hasessentially no meaningful charge-charge or steric hindrance typeinteractions with any opposing nucleoside in a nucleic acid to which thestrand containing the abasic nucleoside binds by means of complementarybase pairing. The moiety in the sugar position in abasic nucleosides,however, can radically depart from normal ribose structure to includenovel five membered or six membered rings or no ring at all as shown inFIG. 10.

“Accommodating Guide Strand Design” or “AGSD” refers to the methods andcompositions provided by the present invention that are not described inthe prior art for ssRNAi compounds. The ssRNAi compounds generated byAGSD are generally referred to as agsRNAi.

“Accommodating guide strand modification” or “accommodatingmodification” or “AGSD modification” refers to one of the specific AGSDmodifications provided for herein. AGSD modifications are not providedby the prior art relating to ssRNAi.

“Activity,” unless otherwise qualified, refers to the maximum ability ofan agsRNAi, ssRNAi, siRNA or miRNA compound to modulate the expressionand/or function of its target. It is the amount of the maximum effect onthe target as determined by the plateau generated by a dose responsecurve for the compound in question. It is typically expressed as apercent change relative to the base line or to a negative control.Activity is to be distinguished from potency.

“AENA” is an abbreviation for a 2′-deoxy-2′-N,4′-C-ethylene-LNA. It isshown in FIG. 7 where B is any of the bases provided for herein.

“AGO-2 based catalytic off-target silencing activity” or any similarstatement refers to situations where an ags-MiR functions as anags-siRNA. Various methods are provided herein to inhibit suchsiRNA-like off-target activity.

“AgsRNAi” is a general term referring to ssRNAi compounds generatedusing AGSD methods and modifications.

“Ags-siRNA” refers to an agsRNAi directed to a nucleic acid target otherthan an miRNA. Ags-siRNAs have the same targeting code as the one foundin siRNA.

“Ags-IMiR” refers to an agsRNAi directed to an miRNA target or to anon-canonical miRNAs target such as a simtron or a mirtron. Ags-IMiRshave the same targeting code as the one found in siRNA.

“Ags-MiR” refers to an agsRNAi that is an miRNA mimic. Ags-MiRs have oneof the targeting codes found in miRNA. It can either mimic a particularnaturally occurring miRNA or it can have a novel targeting code. Ags-MiRcompounds based on a seed sequence targeting code can be based on themodular design approach.

“Algorithms” refers to sets of rules used to design specific aspects ofagsRNAi compounds.

“ALN” is an acronym for α-L-LNA. It has an alpha-L-ribo configurationand is illustrated in FIG. 9 panels A and B along with onephosphodiester linkage and where B is any of the bases provided forherein.

“ANA” is an acronym for altritol nucleic acid. It is illustrated in FIG.4 where B is any of the bases provided for herein.

“Antisense oligo” or “conventional antisense oligo” when not used in thecontext of an RNAi drug or RNAi trigger are single stranded oligos thatinhibit the expression and/or function of a targeted nucleic acid. Suchantisense oligos produce their biologic effects by one of the followingmechanisms: (1) Steric hindrance—e.g., the antisense oligo interfereswith some step in the sequence of events involved in gene expressionand/or production of the encoded protein by directly interfering withone of these steps. Such steps can include transcription of the gene,splicing of the pre-mRNA and translation of the mRNA; (2) Induction ofenzymatic digestion of the RNA transcripts of the targeted gene by RNaseH or other enzyme such as RNase L, RNase P or double stranded RNase; and(3) Combined steric hindrance and induction of enzymatic digestionactivity in the same antisense oligo. Conventional antisense oligos donot have an RNAi mechanism of action as determined by any of a number oftechniques well established in the art.

“Antisense oligo or antisense strand” when used in the context of anRNAi drug or RNAi trigger refers to the guide strand of an RNAi drug orRNAi trigger. “Argonaute” is a family of proteins or a member of thefamily that in humans has four members abbreviated AGO-1 through AGO-4.RISC typically has one such protein that non-covalently binds the guidestrand of an RNAi trigger.

“Backbone” refers to the alternating linker/sugar structure of oligosthat holds the nucleosides in a particular order.

“Base” refers to the component of a nucleoside or nucleoside analog thatwhen incorporated into an oligo can directly engage in complementarybase paring with a nucleic acid. The standard naturally occurring bases(canonical bases) are cytosine, uracil, adenine, guanine and thymine.Certain non-canonical bases are AGSD modifications.

“Basic nuclease resistance” refers to the modifications describedherein, other than AGSD modifications, which must be applied to agsRNAicompounds in order to achieve adequate nuclease resistance for theintended application(s). The basic nuclease resistance modificationscommonly include 2′-fluoro and 2′-O-methyl sugar modifications and caninclude phosphorothioate and other linkages that increase nucleaseresistance compared to the phosphodiester linkage. For agsRNAi compoundsthat will be used with a protective carrier, the level of basic nucleaseresistance can be lower than for compounds that will be used without aprotective carrier. The basic nucleases resistance modifications can beincreased or decreased on an as needed basis for applications thatinvolve differences in the levels of nuclease activity found inparticular organs/tissues/cells and/or in particular species. Linkagesites that are cleaved by nucleases in particular organs/tissues/cellscan be readily determined using a combination of liquid chromatographyand mass spectrometry (LC-MS). Once a cleaved linkage site(s) isidentified the nuclease protection can be increased by changing one orboth of the sugars in the linkage site to a more resistance sugar,including an AGSD sugar, and/or by replacing a phosphodiester linkagewith a phosphorothioate linkage or another linkage providing nucleaseresistance or by replacing a phosphorothioate linkage with one of theother nuclease resistant linkages.

“Carriers” refer to structures that can be used to directly orindirectly facilitate the uptake and/or increase the probability that anassociated agsRNAi, ssRNAi, siRNA or miRNA compound will enter thosecells that are accessible to the carrier/RNAi trigger combination. As aresult of the action of the carrier, the RNAi trigger becomesbioavailable in cells as evidenced by its ability to produce theintended effect(s) on its intracellular target(s). Carriers thatfunction as transfection agents are composed of cationic lipids. Theywill only work in vitro and then only with susceptible cell lines orprimary cell cultures. Carriers for use in subjects typically will onlybe able to access some organ/tissue/cell types in subjects to theexclusion of others and come in several types including the following:(1) those “protective carriers” that envelop the compound and thusprovide added protection from extracellular enzymatic attack until thecompound is released in cells; (2) those “non-protective carriers” thatare associated with the compound but that do not envelop it. Thisassociation can be covalent or non-covalent. This type of carrierincludes those that either: (a) promote the binding of the compound toplasma proteins to a degree that promotes clearance of the compound fromthe general circulation by cells in the body rather than clearance bythe kidney; and/or (b) those that bind to a cell surface receptor thatthen internalizes the carrier/RNAi trigger where the RNAi triggereventually is released into the interior of the cell. Carriers are to bedistinguished from “vehicles” which are ingredients of a drugformulation other than the drug. Vehicles do not function as a carrieras defined here. They can be excipients or materials involved incontrolling the rate of release of the RNAi trigger or other drug intoextracellular fluids.

“Cell line” refers to a population of cells taken from a tissue or anabnormal growth in a subject that has been passaged at least once incell culture. With each subsequent passage (subculture), the cellpopulation becomes more homogeneous as the faster growing cells come topredominate.

“CENA” is an acronym for 2′,4′-carbocyclic-ethylene-bridged or2′,4′-carbocyclic-ENA-locked nucleic acid. It is illustrated in FIG. 1where “base” represents any of the bases provided for herein.

“CeNA” is an acronym for cyclohexenyl nucleic acid. It is illustrated inFIG. 11 where “base” represents any of the bases provided for herein.

“cEt” is Ethyl bicyclic nucleic acid. See FIG. 13B for the structure.

“Chimeric oligonucleotides” or “chimeric oligos” are ones that containribonucleosides as well as 2′-deoxyribonucleosides. In the case ofsiRNA, ags-siRNA and ags-siRNA the guide strand can have one or more2′-deoxyribonucleosides in the seed sequence as one option to reduce anyunintended miRNA-like activity. In the case of agsRNAi contiguous2′-deoxyribonucleosides can be used when joined by a boranophosphatelinkage.

“Cognate” refers to a double stranded siRNA or miRNA that has the sameguide strand sequence and, unless otherwise stated, the same pattern ofmodifications as a corresponding ssRNAi and/or agsRNAi and conversely.Unless otherwise stated the passenger strand in a cognate siRNA or miRNAis fully complementary to the guide strand through nucleoside position19 counting from the 5′-end and it is unmodified. An ssRNAi or agsRNAitypically possesses a phosphate or phosphate analog conjugated to the5′carbon of the 5′end nucleoside while the cognate siRNA or miRNA guidestrand is not required to have such a 5′-carbon modification.

“Compounds” refers to compositions of matter that include agsRNAi,ssRNAi, siRNA and miRNA, as well as to individual guide and passengerstrands.

“CRN” is an acronym for conformationally restricted nucleoside ornucleomonomer as described in WO 2011/139710 except the linkages used toconnect CRNs to other nucleosides in accordance with the presentinvention are not necessarily phosphodiester. CRN nucleosides come intwo basic forms illustrated in FIG. 8. In the R monomer, X can beindependently selected for each occurrence in an agsRNAi compound fromthe group consisting of O, S, CH₂, C═O, C═S, C═CH₂, CHF or CF₂; R₂ andR₃ are the linkages and B is a nucleobase or nucleobase analog where thelinkages, nucleobases or nucleobase analogs are independently selectedfrom the group consisting of those provided for herein. In the Q monomerX and Y can be independently selected for each occurrence from O, S,CH₂, C═O, C═S, C═CH₂, CHF or CF₂; R₁ and R₃ are the linkages, R₂ isindependently selected for each occurrence from the group consisting ofH, F, OH, OCH₃, OCH₃OCH₃, OCH₂CH₃OCH₃, CH₂CH₃OCH₃, CH(OCH₃)CH₃, allylalthough H, F, OH, OCH₃ are preferred; Z is independently selected foreach occurrence from the group consisting of N or CH; and B is anucleobase or nucleobase analog where the linkages, nucleobases ornucleobase analogs are independently selected from the group consistingof those provided for herein.

“Dicer” is a protein that has various capabilities including anenzymatic activity that cleaves double strand RNA precursors to generatesiRNA or miRNA compounds with 3′-end overhangs in cells. It also istypically a component of the RLC. It is capable of binding both doubleand single strand RNA.

“Dose” is given as milligrams or another unit of weight based on gramsof a compound typically divided by the weight of the recipient subjectassumed to be a kilogram such as milligrams per kilogram (mg/kg).

“Drug” can refer either to a pharmaceutical grade product meeting FDAstandards for being called a drug or to a product not manufactured orsynthesized to such standards but that could be. The latter compoundscan be used for non-clinical research purposes.

“EA” is an abbreviation for 2′-aminoethyl nucleoside. It is illustratedin FIG. 5 where B represents any of the bases provided for herein.

“Enveloping carrier,” “protective carrier” or similar phrase refers to acarrier that surrounds one or more RNAi triggers protecting them fromenzymatic attack in extracellular fluid(s) and that promotes theiruptake by one or more organ/tissue/cell types in the body of a subject.

“FANA” or 2′-deoxy-2′fluoro-arabinonucleic acid refers to a nucleosidemodification where the fluorine has the same stereochemical orientationas the 2′-hydroxyl in β-D-arabinofuranose. In instances where thefluorine has the same orientation as the 2′-hydroxyl inβ-D-ribofuranose, the associated nucleoside is referred to as 2′-fluoro.

“F-CeNA” is an acronym for fluoro cyclohexenyl nucleic acid. The basicCeNA structure is illustrated in FIG. 11 where “base” represents any ofthe bases provided for herein. In the case of F-CeNA, which is notillustrated, the fluorine appears in the 2′ position while the base isin the 1′ position.

“FHNA” or “3′-FHNA” is an abbreviation for 3′-fluoro hexitol nucleicacid. The basic HNA nucleoside structure is shown in FIG. 6 where B isone of the bases provided for herein.

“Flexible sugar” is used as is or with modifiers that indicate degreesof flexibility in terms of the ease with which a sugar in a nucleosidechanges its conformation (pucker) in response to outside influences.

“General circulation” or “systemic circulation” refers to the bloodcirculated throughout the body by means of the heart and the associatedsystem of blood vessels. Compounds such as agsRNAi, ssRNAi, siRNA andmiRNA that are administered to a subject in such a way that they enterthe general circulation for distribution to their target cells are saidto be systemically administered. Suitable means of administrationinclude, but are not limited to, intravenous, intra-arterial,intradermal, intramuscular and by inhalation. Administration to thoseareas of the body that are protected by barriers that limit the passagesof such compounds out of the general circulation and into regions of thebody such as the central nervous system, testicles, placenta, fetus andthe interior of the eye (aqueous and vitreous humor) typically requireby passing the barrier for example by injecting a compoundintraventricularly, intrathecally or intranasally.

“Guide strand” is used interchangeably with antisense strand in thecontext of agsRNAi, miRNA, siRNA or ssRNAi compounds. In contrast,antisense oligos or conventional antisense oligos refers to a differentoligo-based drug class.

“Gymnosis” a method of gaining cellular uptake of oligos by cells inculture to effect changes in the expression and/or function of anintracellular target(s) where the uptake is achieved by prolongedincubation of the cells with high concentrations of the oligos. Gymnosisallows oligo uptake to occur that is unassisted by transfection agentsor any mechanical means such as electroporation. It is applicable tonumerous cell types that are not susceptible to these methods allowingthem to be successfully treated with intracellular target modulatingoligos (Stein et al., Nucleic Acids Res 38, No. 1 e3: 1-8,2010-published online Oct. 23, 2009).

“HM” is an abbreviation for the 4′-C-hydroxymethyl-DNA nucleoside shownin FIG. 2 where B is one of the bases provided for herein.

“HNA” is an abbreviation for hexitol nucleic acid and includes thenucleoside shown in FIG. 6A where B is one of the bases provided forherein and it is conjugated to the 2′ position carbon of the ring.

“Inhibit expression” or “inhibition of expression” refers to a reductionin the level of expression of a target nucleic acid or its product. Itcan involve, for example, a reduction in target RNA levels, demonstrateddegradation of an RNA target, a reduction in an gene transcript,reduction in protein synthesis where the target is an mRNA encoding theprotein or all of the above.

“Internal linkage sites” refers to linkage sites that are not at thevery 5′ or 3′-end of an agsRNAi or ssRNAi. These sites are potentiallysubject to single strand endonuclease attack. Along with the very 5′-and 3′-end linkages, internal linkage sites may also be simply referredto as linkage sites.

iPS cell or iPSC are abbreviations for induced pluripotent stem cells.They are created (induced) from somatic cells by experimentalmanipulation. “Pluripotent” refers to the fact that such stem cells canproduce daughter cells committed to one of multiple possibledifferentiation programs.

“Kit” refers to the drug combination of an agsRNAi and its passengerstrand where these two drugs are administered sequentially typically toa subject. It is not meant to imply that these two drugs have to bepackaged and/or sold together as a single unit. Kits can also compriseagsRNAi of the invention in single stranded from in the absence of apassenger strand.

“Linkage site” refers to a particular linkage site or type of linkagesite within an agsRNAi, ssRNAi or other oligo. A linkage site is definedby its the linkage and the identities of the contiguous 5′ and 3′nucleosides or in the case of an overhang precursor the units. Linkagesites generally can be designated by “X-Y” where X and Y each representnucleosides with one of the normal bases (A, C, G, T or U) or otherbases provided for herein or nucleosides and the dash indicates thelinkage between them.

“LNA” is the acronym for locked nucleic acid. Standard LNA and threecommon variants are illustrated in FIG. 9 along with one phosphodiesterlinkage where “base” or B represents any of the bases provided forherein. These are standard LNA, thio-LNA and amino-LNA and alpha-L-LNA.The latter also can be referred to as ALN. Unless otherwise stated whenLNA is referred to it should be interpreted as referring to standardLNA.

“Mismatch” refers to a nucleoside in an agsRNAi or ssRNAi compound thatdoes not undergo complementary base pairing with the target(s) of thecompound.

“MicroRNAs (miRNAs)” are a category of naturally occurring RNAi triggerthat typically cause the post-transcriptional repression of proteinencoding genes after the guide strand is loaded into RISC. Uncommonly,some miRNAs can also cause the increased expression of their RNA targetand/or modulate the function of their target(s) in a positive ornegative direction. The miRNA guide strand directs RISC to specific RNAtargets as recognized by the targeting code. Most commonly the seedsequence recognizes completely matched sequences in the 3′UTR of mRNAstranscribed from multiple different genes.

“MicroRNA mimics or miRNA mimics” are a category of manufacturedcompounds that when administered to cells in vitro or cells in subjectsutilize the cellular mechanisms involved in implementing the activity ofnaturally occurring miRNA in order to produce a modulation in theexpression and/or function of a particular set of RNA and/or genetargets. MicroRNA mimics of the present invention (ags-MiRs), likeconventional double strand miRNA mimics, can be designed to modulatesome or all of the same targets modulated by a particular naturallyoccurring miRNA. When based on an endogenous miRNA, an ags-MiR will havethe same targeting code as the endogenous miRNA. The rest of thecompound may have all, some or none of the sequence found in theendogenous miRNA from which the targeting code sequence was taken.Ags-MiRs also can be designed to modulate the expression of a set of RNAand/or gene targets by using a novel targeting code sequence not foundin any know endogenous miRNA.

“miRNA” refers to one of the two major types of double strand RNAitriggers. The other major type is siRNA. miRNA and siRNA arestructurally basically the same and they engage the RNAi mechanism andare processed in the same way but they have different targeting codes.They typically instigate different post-target engagement RNAimechanisms that effect target expression and/or function. Mirtrons andsimtrons are non-canonical miRNAs.

“Mirtron” refers to a non-canonical miRNA that has a pre-miRNA that isdefined by the entire length of the intron in which it is located. Itrequires pre-mRNA splicing rather than the miRNA microprocessor as aninitial step in its production (Havens et al., Nucleic Acids Res 40:4626-40, 2012; Curtis et al., Wiley Interdiscip Rev RNA 3: 617-32,2012).

“Mismatch” refers to a nucleoside in an oligo that does not undergocomplementary base pairing with the nucleoside opposite to it when theoligo binds, on the basis of complementary base pairing, to anothernucleic acid or to itself when it forms a hairpin. Mismatches includethose that can occur between canonical bases (such as A:G, A:C, G:G,G:A, A:A, U:U, C:C and C:U), two non-canonical bases, a canonical andnon-canonical base as well as between an abasic nucleoside and acanonical or non-canonical base. In addition, the mismatch can involve anucleoside with a chemical moiety in the position of the base that isnot normally part of any natural nucleic acid and where the moiety doesnot undergo an attractive charge/charge interaction with an opposingcanonical or non-canonical base. Examples of such moieties are providedin WO 2010/011895 and include a nucleoside with a 2,4 difluorotoyl baseand a nucleoside with a 5-nitroindole base.

“Modification” is a structure added to or inserted during themanufacture or synthesis of an RNAi trigger or RNAi drug. Unmodifieddouble strand and single strand RNAi triggers are oligoribonucleotideswhere the oligoribonucleotide is comprised of some combination of thecommon naturally occurring ribonucleosides (adenosine, guanosine,uridine, and cytidine) joined by phosphodiester linkages. In addition,natural double strand triggers and most chemically generated ssRNAicompounds have a 5′-end phosphate. 5′-end phosphate substantially booststhe activity of ssRNAi but this moiety is not necessary for siRNA ormiRNA.

“Modified linkage” refers to a linkage between nucleosides and/or unitsprovided for herein that is not a phosphodiester.

“Modulate,” “modulating” or “modulation” refer to changing the rate atwhich a particular process occurs, inhibiting or accelerating aparticular process, redirecting a particular process, and/or preventingor promoting the initiation of a particular cellular process, e.g.,cellular signaling, protein transport, drug efflux, cell growth,morphological alterations, differentiation etc.

“Modular design” or “modular approach” refers to an approach forgenerating ags-MiRs or ssRNAi compounds that are miRNA mimics where thetargeting code is the seed sequence. According to modular design thecompound is divided into three modules that can be independentlymanipulated where the positions of the modules are as follows: (1) the“5′-end module” consisting of nucleoside positions 1-8 or 1-9; (2) the“seed vehicle” consisting of nucleosides 9-19 or 10-19 depending on thelength of the 5′-end module; and (3) an optional overhang precursorcomprising nucleosides and/or units starting in position 20 andcontinuing up to position 23 depending on its length.

“Moiety” refers to a part of a molecule, such as a nucleoside, sugar,base, linkage, agsRNAi or ssRNAi, which exhibits a particular set ofchemical and/or pharmacologic properties.

“Newer ssRNAi” refers to the ssRNAi compositions described in Haringsmaet al., Nucleic Acids Res 40: 4125-37, 2012; Yu et al., Cell 150:895-908, 2012; Chorn et al., RNA 18: 96-804, 2012; Lima et al., Cell150: 883-94, 2012; WO 2011/046983; WO 2011/139699; WO 2011/139702; andWO 2012/027206.

“Nuclease resistant linkage” refers to one of the linkages providedherein that are more nuclease resistant than phosphodiester.

“Nucleoside” refers to any one of the structures that can appear inpositions 1-19 counting from the 5′-end of the RNAi triggers describedherein. These structures include natural nucleosides, nucleosides withnon-canonical basis and/or sugar analogs or sugar substitutes as well asabasic nucleosides that can lack any ringed structure as shown in oneexample in FIG. 10. Leaving aside the linkages overhang precursorsconsist in part or entirely of nucleosides. The structures in overhangprecursors that are nucleosides can also be called units while othercomponent structures that are not nucleosides are necessarily calledunits.

“Off-target silencing or effects due to the seed sequence” or anysimilar statement refers to situations where the seed sequence an RNAitrigger intended to only have siRNA or siRNA-like activity directs RISCto unintended targets that are then silenced by a miRNA mechanism.Various methods are provided herein to inhibit such seed sequence basedoff-target activity by agsRNAi. These include using a nucleoside inposition 2 that has a 2′ modification of the size of a methyl group orlarger and/or by using modifications provided herein that reduce theaffinity between the seed region and the unintended targets. Thesesmodification(s) can reduce the off-target inhibition of 1, 2, 3, 4, 5 orgreater than 5 targets engaged by the seed region by 20, 30, 40, 50, 60,70, 80, 90 or >90% compared to compounds without the modification.

“Oligonucleotide” or “oligo” refers to a strand of ribonucleosidesand/or ribonucleoside analogs and/or 2′-deoxyribonucleosides and/or2′-deoxyribonucleoside analogs comprising about 13 to 30 nucleosidesthat are linked by phosphodiester and/or by nuclease resistant linkages.

“Oligoribonucleotide” refers to an oligo where the nucleosides areribonucleosides or ribonucleoside analogs such as 2′-fluoro and2′-O-methyl. A ribonucleoside is one in which the sugar is more likelyin the C3′-endo conformation when tested alone or as part of a linkedmulti-ribonucleotide strand.

The phrase “operably linked” means that the sequences necessary areplaced in the nucleic acid molecule in the appropriate positions so asto effect expression of the sequence. This same definition is sometimesapplied to the arrangement of coding sequences and transcription controlelements (e.g. promoters, enhancers, and termination elements) in anexpression vector. This definition is also sometimes applied to thearrangement of nucleic acid sequences of a modular nature wherein ahybrid nucleic acid molecule of modules is generated.

“Organ” is a group of tissues that are a discrete structural unit in thebody that performs a specific function or set of functions. Examplesinclude but are not limited to liver, kidney, lung, spleen, pancreas,brain, stomach, prostate, uterus, ovary, gall bladder, heart, bladder,esophagus, duodenum, jejunum, ileum, colon, testis, skin, and eye.Details and other examples are provided by standard medical texts ofanatomy and histology such as “Junqueira's Basic Histology: Text andAtlas,” Anthony Mescher (Author), McGraw-Hill Medical; ThirteenthEdition, February 2013.

“Overhang,” in the context of siRNA and miRNA, refers to any portion ofthe passenger and/or guide strand that extends beyond the duplex formedby these strands. In the case of natural RNAi triggers, both strandshave 3′-end overhangs that are typically two nucleosides in length.siRNA and miRNA drugs, however, can have 5′ and/or 3′-end overhangs onone or both strands that are 1-4 nucleosides and/or units in length orhave no overhang(s).

“Overhang precursor” refers to that portion, if any, of an agsRNAi orssRNAi that would form an overhang if combined with a 19-mer partnerpassenger strand capable of forming a duplex with the agsRNAi or ssRNAinucleosides in positions 1-19. Overhang precursors are 1-4 nucleosidesand/or units in length. They can engage the PAZ domain of Dicer and/oran argonaute protein but do not directly engage the agsRNAi target(s).

“Parenchyma” refers to the defining essential and distinctive cell typefound in an organ, gland or neoplastic growth. In each of theseinstances the parenchymal cells are distinguished from its supportiveframework including such elements as connective and vascular tissue andin some instances stromal cells. The parenchymal cells of a particularorgan may or may not also be formally classifiable as one of the threegeneral tissue types, i.e., epithelial, nervous or muscle. Strictlyspeaking some other parenchymal cells, such as hepatocytes do not fallinto one of the categories of tissue types. Nevertheless, they are notuncommonly referred to by the name of the organ followed by the wordtissue, e.g., liver tissue. Details and more examples are provided bystandard medical texts of anatomy and histology such as “Junqueira'sBasic Histology: Text and Atlas,” Anthony Mescher (Author), McGraw-HillMedical; Thirteenth Edition, February 2013.

“Passenger strand” is used interchangeably with “sense strand” in thecontext of miRNA or siRNA compounds. It forms a duplex with its partnerguide or antisense strand on the basis of complementary base pairing toform one of these double strand compounds.

“Pharmacologically effective amount,” “therapeutically effective amount”or simply “effective amount” refers to that amount of an agent effectiveto produce a commercially viable pharmacological, therapeutic,preventive or other commercial result.

“Potency” describes the activity of an agsRNAi, ssRNAi, siRNA or miRNAcompound expressed in terms of the amount required to produce a givenlevel of activity under certain defined circumstances. Potency providesa useful basis for comparing drugs with a common mechanism-of-action.Typically it is defined in terms of the molar concentration (molarity)of the compound or the amount of the compound divided by a measure ofweight correlated with the subject or solid tissue sample being treatedby the compound. For example, a 20-gram mouse systemically treated with0.1 mg of an agsRNAi can be said to have been treated with 5 mg/kg ofthe compound. A higher potency compound evokes a larger response at agiven molar concentration or amount per subject (or tissue sampleweight) while a lower potency compound evokes a smaller or no responseat the same total amount as the higher potency compound whenadministered under the same experimental conditions. Potency istypically measured using a dose response curve for the compoundadministered in vitro or to a subject and measured a specified timeafter the last treatment with the compound. The half maximal inhibitoryconcentration (IC₅₀) is a measure of the effectiveness of a compound ininhibiting the expression and/or function of its target. The halfmaximal effective concentration (EC₅₀) is a measure of the effectivenessof a compound in modulating the expression and/or function of itstarget. EC₅₀, however, is typically used to describe the effect of acompound that promotes the expression and/or function of the target. ICand EC measurements can also be used for other levels of activity wherean alternative percent of the maximal level of change replaces thesubscripted 50, for example IC₇₅ would represent 75% of the maximalinhibitory activity. Two different compounds directed with the samemechanism-of-action can have the same level of activity, for example,both can suppress the expression of their target by 90% in a subject butthey can very greatly in potency, i.e., one produces the 90% suppressionat 1 mg/kg while the other does so at 100 mg/kg. In this example therewould be a 100× difference in potency.

“Primary cells” are cells taken directly from a tissue or neoplasticgrowth in a subject and placed in tissue culture and that have not beenpassaged. A primary cell culture may be composed of mixtures of celltypes, however, appropriate laboratory procedures often can be used toenrich a desired cell type, such as the parenchymal cells, from themixture.

“Prodrug” refers to a compound that is administered to a subject in aform that is inactive but becomes active in the body after undergoingchemical modifications typically through intracellular metabolicprocesses.

“Protective carrier” or “enveloping carrier” refers to a type ofcarrier, such as a lipid nanoparticle, that can provide protection toRNAi triggers by enveloping them. This is particularly important forthose triggers that lack sufficient intrinsic resistance toextracellular enzymes to allow them to be administered systemically.Such protection lasts until the RNAi trigger is released inside ofcells.

“Purine rich region,” unless otherwise stated herein, is defined as asub-region within nucleoside positions 2-19 of an agsRNAi where thereare 3 or more contiguous nucleosides that have a purine base or 4contiguous nucleosides where 3 of them have a purine base.

“Ribose” refers to β-D-ribofuranose.

“RISC” stands for “RNA induced silencing complex.” It typically includesmultiple molecular components including an argonaute protein. The guidestrand of an RNAi trigger is loaded into RISC often with the assistanceof a RLC and this strand guides RISC to the target(s) to be engaged bythe RNAi mechanism.

“Risk loading complex” (RLC) refers to a molecular complex that can binda double or single strand RNAi trigger and subsequently present it toRISC in a manner that promotes the loading of RISC with the guidestrand.

“RNAi” is an abbreviation for “RNA mediated interference” or “RNAinterference.” It refers to the system of cellular mechanisms (RNAimechanism) that can produce RNAi triggers and that engages the guidestrand of an RNAi triggers for modulation of the expression and/orfunction of susceptible nucleic acid targets.

“RNAi activity” refers to the action of the RNAi mechanism on itstarget(s) as directed by the guide strand of the RNAi trigger.

“RNAi drug” strictly speaking refers to a pharmaceutical gradetherapeutic but loosely can be used to describe a non-pharmaceuticalgrade manufactured or synthesized RNAi trigger used in non-clinicalresearch.

“RNAi mechanism” or “RNAi machinery” refers to the cellular moleculesand processes primarily involved in generating RNAi triggers and/ordiscarding the passenger strand while the guide strand is loaded intothe argonaute component of RISC and/or the engagement by the guidedirected RISC and the mechanisms and molecule involved in producing achange in the expression and/or function of the nucleic acid target(s).

“RNAi trigger” refers to single (agsRNAi and ssRNAi) and double stranded(siRNA and miRNA) oligoribonucleotides or chimeric oligos most commonlyin the 19-23-mer-size range that directs the RNAi mechanism toparticular targets. In the case of a double stranded RNAi trigger thepassenger strand (sense strand) is discarded at some point during theprocess of loading the guide strand into the argonaute component ofRISC. The guide (antisense strand) then directs the RNAi mechanism toits target(s). This term applies to naturally occurring siRNA and miRNAas well as to manufactured or synthesized siRNA, miRNA, agsRNAi andssRNAi. The manufactured or synthesized compounds can exist as eitherpharmaceutical grade drugs or as non-pharmaceutical grade drugs for usessuch as non-clinical research.

“Seed sequence” or “seed region” is the region comprised of the 6-7contiguous nucleosides in positions 2-7 or 2-8 counting in from the5′-end of the guide strand of an RNAi trigger. In the case of a miRNA,ssRNAi that functions as a miRNA mimic or an ags-MiR it is also referredto as the “targeting code.”

“Seed vehicle” is used to describe the region of an ags-MiR or ssRNAiconstructed according to the modular design approach other than thosenucleosides in positions 1-9 or 1-8 comprising the 5′-end module andother than any overhang precursor. Hence it is comprised of thenucleosides in positions 10-19 or 9-19 depending on the length of the5′-end module.

“Significant” or “significantly” when used in the context of a change inthe level of function in a RNAi trigger as a result of some modificationor set of modifications refers to an incremental change in activity,potency and/or duration of effect on a target having a minimumincremental change as provided for herein for comparing one agsRNAicompound to another or to an ssRNAi with the same sequence but withmodifications known in the prior art. These minimal incremental changesare stated in the Summary of the Invention. In other instances“significant” refers to statistical significance.

“Silencing” or “silencing activity” traditionally refers to theinhibition of target expression and/or function that occurs as a resultof RNAi activity. It is now clear, however, that RNAi activity cansometimes boost the expression and/or function of its target(s). So anysuch enhancing activity is included under silencing as used herein.

“Simtron” refers to a non-canonical microRNA similar to mirtrons that donot require splicing for their biogenesis (Havens et al., Nucleic AcidsRes 40: 4626-40, 2012).

“seqRNAi” refers to technology first described in WO 2011/046983 and WO2012/145729 where the passenger and guide strands of an RNAi trigger canbe administered sequentially to a subject at a sufficient interval toallow the first strand to be taken up by a wide range oforgan/tissue/cell types before the second is administered. This providesa means for achieving RNAi activity in most organ/tissue/cell types inthe body without the need for a carrier. As for agsRNAi, seqRNAicompounds are divided into three basic types: (1) those that have ansiRNA targeting code but target some nucleic acid other than miRNA(seq-siRNA); (2) those that have an siRNA targeting code and targetmiRNA (seq-IMiRs); and (3) those that have an miRNA targeting code andmimic an endogenous miRNA or have a novel miRNA targeting code sequence.

“siRNA” refers to one of the two major types of double strand RNAitriggers. The other major type is miRNA. miRNA and siRNA arestructurally basically the same and they engage the RNAi mechanism andare processed in the same way but they have different targeting codes.They typically instigate different post-target engagement RNAimechanisms that effect target expression and/or function.

“ssRNAi” or “ss-RNAi” refers to a guide strand only RNAi trigger thatdoes not have to be used with a passenger strand.

“Stem cell” refers to a rare cell type in the body that exhibits acapacity for self-renewal. When a stem cell divides the resultingdaughter cells are either committed to undergoing a particulardifferentiation program or they are the product of self-renewal of theparent stem cell in which case they constitute a replica of the parentstem cell. By undergoing self-renewal, stem cells function as the sourcematerial for the maintenance and/or expansion of a particular tissue orcell type.

“Subject” refers to mammals and in particular those commonly treatedwith therapeutic agents and/or commonly used as models during thedevelopment of therapeutic agents. Subjects include dogs, cats, rabbits,mice, rats, hamsters, guinea pigs, miniature pigs, ferrets, non-humanprimates and humans as well as farm animals including horses, cattle,pigs, sheep and chickens. Subjects include individuals who are normal,suffering from a particular medical disorder, genetically modified orare models of a particular medical indication.

“Subject cells” or a similar phrase refers to one or more particularcell types found in subject or derived from a subject. Such cells can beselected from the group consisting of the following: a particular cellline; a representative sampling of a particular organ, gland or type ofneoplastic growth; an enriched sample of parenchymal cells from aparticular organ, gland or type of neoplastic growth; a particular typeof epithelial tissue including simple, stratified, pseudostratified andtransitional; a particular type of connective tissue where the types areloose and dense forms with the latter being further subdivided intodense regular and dense irregular, other types of connective tissueinclude reticular connective tissue, adipose tissue, blood and lymphoidtissue; a particular type of nervous tissue subdivided by location (suchas brain, spinal cord, ganglion, and nerve) and/or by cell type, i.e.,neuronal or glial; and a particular type of muscle tissue where thetypes are skeletal, cardiac and smooth. Cells of one of these generaltypes can be further subdivided into subsets of cells with definedmolecular and/or functional characteristics by methods known in the art.Further, subject cells can be normal or abnormal. Unless otherwisestated or implied by the context the term “subject cells” applies toboth normal and abnormal cells. Distinguishing between subject celltypes is important for comparing the effects of particular agsRNAi,agsRNAi/passenger strand combinations and ssRNAi compounds on theirtargets and the relative abilities of particular cell types to take upand metabolize such compounds.

“Sugar,” “sugar analog,” “sugar substitute” or “modified sugar” refersto the component of a nucleoside that occupies the functional positionof a ribose or 2′-deoxyribose sugar in a naturally occurring nucleoside.For simplicity the word sugar as used herein can refer to a sugaranalog, sugar substitute, or modified sugar as well as to actual sugars.Thus, the word sugar can be applied to a sugar analog, sugar substitute,or modified sugar that is a AGSD modification as well as to sugars thatare not AGSD modifications. Examples of sugars that are not AGSDmodifications are normal ribose and 2′-deoxyribose as well as 2′-fluoro,2′-O-methyl and 2′-methoxyethyl ribose modifications. Hence the term“sugar” as it is used herein is not meant to have the same definition asthe term sugar that is used in chemistry.

“Synthetic” means chemically or enzymatically manufactured or producedby man and isolated for use as a drug.

“Targeting code” refers to the portion of the guide strand sequence inan agsRNAi, ssRNAi, siRNA or miRNA that is primarily or exclusivelyresponsible for directing RISC to a specific target(s). The term doesnot refer to any particular sequence of nucleosides. Targeting codestypically can be distinguished on the basis of their positions withinthe guide strand relative to its 5′-end. Ags-MiRs as well as ssRNAicompounds with miRNA activity and miRNA itself have one of two possibletargeting codes. One of these targeting codes is referred to as the seedsequence. The seed sequence comprises either 6 or 7 consecutivenucleotides beginning at position 2 counting from the 5′-end and runningto position 7 or 8. The second targeting code is 11 or 12 consecutivenucleosides in length beginning at position 4 or 5 from the 5′-endalthough optionally position 8 or 9 can have a base mismatch with thetarget. Ags-siRNA, ags-IMiRs as well as ssRNAi compounds with siRNAactivity and siRNA itself have a targeting code that is 15 consecutivenucleosides in length extending from position 2 through position 16counting from the 5′-end although optionally position 8 or 9 can have abase mismatch with the target.

“Target nucleic acid” refers to a target for an RNAi trigger. Withrespect to the agsRNAi such targets include but are not limited togenes, mRNA, miRNA and other regulatory non-coding RNA. Despite commonusage of “non-coding RNA,” it has been discovered that some non-codingRNA actually are coding in at least some cellular environments. AgsRNAinon-coding RNA targets include but are not limited to lncRNA, promoterassociated RNA, enhancer RNA, snoRNA, piRNA, xiRNA, sdRNA, moRNA,MSY-RNA, tel-sRNA, crasiRNA and endogenous antisense RNA. Some agsRNAican produce a change in expression of and/or modulate the function ofgenes by directly engaging DNA targets on the basis of complementarybase pairing including but not limited to one or more entitiescontrolling particular gene(s) and selected from the group promoters,enhancers or suppressors.

“Tissue” is an aggregation of similar cells that together perform acertain specialized function(s). Tissues can broadly be classified into4 basic types, which are epithelial, connective, nervous and muscle.There are two types of epithelial tissues: (1) Those that cover theoutside surfaces of the body and line internal organs. This typeprotects the body from things such as moisture loss, bacteria andtrauma; and (2) glandular epithelium that secretes products such ashormones, stomach acid, sweat, saliva and milk. Connective tissueprovides structure and support to the body. The types of connectivetissue can be broadly subdivided into connective tissue proper, specialconnective tissue and a series of other special types of connectivetissue. Connective tissue proper consists of loose and dense forms withthe latter being further subdivided into dense regular and denseirregular. The special types of connective tissue include reticularconnective tissue, adipose tissue, cartilage, bone, blood and lymphoid.Nervous tissue occurs in two types, which are neurons and neuroglia.Muscle tissue occurs as skeletal, cardiac and smooth types. Organsamples are also sometimes loosely referred to by using the name of theorgan with the word tissue, for example, liver tissue or lung tissue.Strictly speaking, however, the definitive cell types in an organ arereferred to as parenchymal cells. Parenchymal cells of the liver, forexample, are hepatocytes and strictly speaking they do not fall into anyof the four formally defined types of tissue. Details and additionalexamples are provided by standard medical texts of anatomy and histologysuch as “Junqueira's Basic Histology: Text and Atlas,” Anthony Mescher(Author), McGraw-Hill Medical; Thirteenth Edition, February 2013.

“Tm” or melting temperature is the midpoint of the temperature rangeover which an oligo separates from a complementary nucleotide sequenceor where complementary sequences within the oligo itself (hairpin) areseparated. At this temperature, 50% hybridized and 50% unhybridizedforms are present. Tm can be measured by using the UV spectrum todetermine the formation and breakdown (melting) of hybridization usingtechniques that are well known in the art. There are also formulasavailable for estimating Tm on the basis of nearest neighbor analysis orin the case of very short duplexes in accordance with the relative G:Cand U:A content. For the purposes of the present invention Tmmeasurements are based on physiological pH (about 7.4) and saltconcentrations (about 150 mM).

“Transfection” refers to a method for facilitating the passage ofoligos, such as RNAi triggers, across the membrane of susceptible cellsgrown in tissue culture. The method involves incubating the oligo(s)with a transfection agent and then applying the mixture to the surfaceof cells for a period of time followed by the removal of thetransfection agent by washing. The transfection agents are cationiclipids that form liposomes that fuse with the membranes of cells anddeposit the RNAi trigger inside them. Such transfection agents are notsuitable for use in subjects and are to be distinguished from carriersthat are used for that purpose. “Treatment” refers to the application oradministration of an RNAi trigger or RNAi drug to a subject or patient,or to an isolated tissue, primary cell sample or cell line from asubject or patient.

“UNA” is an acronym for unlocked nucleic acid or nucleoside. The ribosesugar ring in the nucleoside is acyclic by virtue of lacking the bondbetween the 2′ and 3′ carbon atoms as shown in FIG. 3 where B representsany of the bases provided for herein.

“Unacceptably stimulates innate immune response” or any similarstatement refers to situations where certain nucleosides in the ssRNAistrand, such as some of those where U, A or G are coupled with ribose orto a lesser extent 2′-fluoro, activate the release of inflammatorycytokines (such as TNF-α, IL-1, IL-6, IL-12 and IL-16) from cells as aresult of stimulating receptors involved in the innate immune responsesuch as TLR 7 and 8. Various well-established assays are available tomonitor the effects of oligoribonucleotides, chimeric oligonucleotidesand other compounds on innate immunity. The induction of innate immunitybecomes a problem when it produces unacceptable side-effects in subjectssuch as fever, chills and weight loss. Methods provided herein toinhibit such immune stimulation include the selective use of the2′-O-methyl modification. The modification(s) provided for this purposecan reduce levels of cytokine(s) induced by the innate immune system by20, 30, 40, 50, 60, 70, 80, 90 or >90% compared to otherwise identicalcompounds without the modification(s).

“Unit” refers to the nucleosides and/or to linked non-nucleosidemoieties that appear in overhang precursors. These non-nucleosidemoieties are limited to those structures provided for herein which areonly allowed in overhang precursors.

“Unless otherwise specified” or “unless otherwise provided for” refersto other specified modifications described herein that provide for adifferent modification(s) under certain circumstances. In these and inother instances where two or more rules specifying differentmodifications for the same entity, the more narrowly applicable rule(applies to fewer agsRNAi strands) dominates.

“Upstream” and “Downstream” respectively refer to moving along anucleotide strand in a 3′ to 5′ direction or a 5′ to 3′ directionrespectively.

“Vehicle” refers a substance of no therapeutic effect that does not actas a “carrier” as defined here but is used to convey an active medicineor compound such as an RNAi trigger. An example of a vehicle suitablefor use with the compounds of the present invention is buffered saline.The term vehicle also includes substances in which a drug can besuspended or dissolved that provide for the release of the drug overtime.

C. The Embodiments

In one embodiment, AGSD methods and modifications are applied to ssRNAiin order to produce novel ssRNAi compounds (agsRNAi) with increasedactivity, potency and/or duration of the effect on the target(s).AgsRNAi targets are typically RNA and include pre-mRNA, mRNA andnon-coding regulatory RNAs. Non-coding regulatory RNA targets includebut are not limited to lncRNA, promoter associated RNA, enhancer RNA,snoRNA, piRNA, xiRNA, sdRNA, moRNA, MSY-RNA, tel-sRNA, crasiRNA andendogenous antisense RNA. Included among the non-coding RNA targets arethose that, at least in some cellular environments, can have codingactivity. Some agsRNAi compounds can produce a change in expression ofand/or modulate the function of genes by directly engaging DNA targetson the basis of complementary base pairing including but not limited toone or more entities controlling particular gene(s) and selected fromthe group promoters, enhancers or suppressors. AgsRNAi uses includethose involving therapeutics, diagnostics, target validation for drugdevelopment, functional genomics, genetic engineering andpharmacogenomics.

In a related embodiment the agsRNAi shares a targeting code with siRNA(ags-siRNA). In another related embodiment the agsRNAi is a miRNAinhibitor (ags-IMiR) that shares a targeting code with siRNA. In anotherrelated embodiment the agsRNAi is a miRNA or miRNA-like mimic (ags-MiR).Ags-MIRs can have a seed sequence taken from a known endogenous miRNA orhave a novel seed sequence. The nucleosides in the seed sequence can bemodified to increase or decrease their binding affinity with one or moreof their target(s). Outside of the seed sequence they can have asequence that is based on the sequence of the endogenous miRNA beingmimicked or can have additional sequences based on the modular designapproach. As an alternative to a seed sequence based targeting code anags-MiR can have a targeting code that encompasses the 11 or 12consecutive nucleosides beginning at position 4 or 5 counting from the5′-end. In another related embodiment the agsRNAi is administered to asubject without a carrier. In another related embodiment the agsRNAi isadministered to a subject with a carrier. In another related embodimentthe agsRNAi is administered to cells in vitro. In another relatedembodiment the agsRNAi has a 5′-end phosphate or 5′-end phosphateanalog. In another related embodiment the agsRNAi nucleosides inpositions 1 and 2 and their intervening linkage are permissive for anintracellular kinase in a cell in a subject adding a 5′-phosphate to the5′-carbon of the 5′-end nucleoside intracellularly. In another relatedembodiment the agsRNAi nucleosides in positions 1 and 2 and theirintervening linkage are not permissive for an intracellular and/orextracellular phosphatase in a subject removing a 5′-phosphate or5′phosphate analog from the 5′-carbon of the 5′-end nucleoside. Any suchphosphatase effect can be limited to intracellular phosphatases by usingan enveloping carrier to deliver the agsRNAi to the interior of cells ina subject. In another related embodiment the agsRNAi has an overhangprecursor of 1-4 units in length. In yet another embodiment an agsRNAican be administered to a cell in a subject or in vitro with a passengerstrand that is unmodified or is modified using methods and compositionsknown in the art. In a related embodiment an agsRNAi that is suitablefor administration to a subject without an enveloping carrier can besequentially administered to a cell in a subject or in vitro inassociation with a passenger strand that is modified using methods andcompositions known in the art for administration to a subject withoutthe use of an enveloping carrier (WO 2011/046983; WO 2012/145729). Inanother related embodiment the agsRNAi compounds can be delivered tocells in subjects using a protective carrier that delivers the agsRNAito some organs/tissues/cell types in the body to the exclusion ofothers. In still another embodiment the agsRNAi compounds can bedelivered to cells in subjects using a carrier that is not protectivethat selectively delivers the agsRNAi to targeted organs/tissues/celltypes in the body to the exclusion of others.

D. Designing AgsRNAi Compounds Providing Basic Nuclease Resistance

Two groups have generated data showing that either of two differentpatterns of modification can provide sufficient basic nucleaseresistance to obtain substantial ssRNAi activity in cultured cellsand/or in mice. In both instances, the ssRNAi compounds were 21-mers andmultiple compounds were tested confirming the general applicability ofthese designs.

In one design the modifications are as follows: (1) A 5′-end phosphate(2) 2′-fluoro nucleosides in positions 1-19; (3) An overhang precursorcomprising two uridines with the 2′-O-methyl modification; and (4) Allof the linkages were phosphodiester (Haringsma et al., Nucleic Acids Res40: 4125-37, 2012; Chorn et al., RNA 18: 96-804, 2012). Compounds basedon this design had to be delivered to liver cells in mice using aprotective lipid nanoparticle because they were not sufficientlyresistant to extracellular nucleases and because the phosphodiesterlinkage does not sufficiently adhere to plasma proteins to avoid rapidclearance by the kidneys when the compound is systemically administered.

In the other design the modifications are as follows:

(1) A 5′-end phosphate conjugated to either a uridine with a 2′-O-methylmodification or a thymidine with a 2′-O-methyoxythyl modification.Either of these gave the best results when the ssRNAi compounds weretransfected into a cell line. When administered to mice, however, the5′-end phosphate was removed in the liver and these compounds were notactive. The investigators were able to get activity in the liver ofanimals by using a 5′-end phosphate analog called 5′-VP conjugated to athymidine with a 2′-O-methyoxythyl modification. It is much less activethan 5′-end phosphate, however, in cultured cells;(2) 2′-fluoro alternating with 2′-O-methyl nucleosides in positions 2-19with the 2′-fluoro being in the even numbered positions;(3) An overhang precursor comprising two adenosines with the2′-O-methyoxythyl modification was present with phosphorothioatelinkages connecting them together as well as to the rest of the ssRNAi;and(4) having phosphorothioate linkages between nucleoside positions 1-2,2-3, 4-5, 6-7, 8-9, 10-11, 12-13, 14-15, 15-16, 16-17, 17-18 and 18-19with phosphodiester linkages in positions 3-4, 5-6, 7-8, 9-10, 11-12 and13-14 (Lima et al., Cell 150: 883-94, 2012; Yu et al., Cell 150:895-908, 2012). Thus, there was a total of 14 phosphorothioate linkagesin these ssRNAi compounds. They were administered to mice either withouta carrier or with a C16 non-enveloping carrier that increased thebinding of these compounds to plasma proteins. The effect of this was toreduce the clearance of these compounds from the plasma by the kidneysand thereby allowing more of the compound to be taken up by cells in themice.

These designs for providing basic nuclease resistance to ssRNAicompounds can be used as a starting point for providing basic nucleaseresistance to agsRNAi compounds, but these designs do not have to berigidly followed. The modifications provided for nucleoside positions2-19 by these designs in particular are a useful, but not necessary,starting point for the generation of agsRNAi compounds.

Once a particular set of modifications providing basic nucleaseresistance are provided then the AGSD modifications are added. In mostinstances AGSD modifications would provide enhanced nuclease protectionrelative to the basic nuclease protection for the linkage sites wherethey appear.

The level of basic nuclease resistance for agsRNAi compounds is directlyrelated to how and where the compounds are to be administered. When theyare to be systemically administered with or without a protective carrierthe basic nuclease resistance provided must be sufficient to protect thecompounds from extracellular nucleases including those in plasma. Whenthey are systemically administered with a protective carrier the levelof basic nuclease protection can be less.

The methods for providing basic nuclease resistance described below arelimited to nucleoside positions 2-19. Options for modifying thenucleoside in position 1 are provided in the section “Designing AgsRNAiCompounds: 5′-End Modifications.” Options for overhang precursors areprovided in the section “Designing AgsRNAi Compounds: OverhangPrecursors.”

Providing basic nuclease resistance to nucleoside positions 2-19 ofagsRNAi compounds to be used with a protective carrier can be achievedby one of the following sets of modifications:

Set 1: All of the nucleosides in positions 2-19 can be 2′-fluoro and allof the linkages phosphodiester.

Set 2: The nucleosides in positions 2-19 can be 2′-fluoro alternatedwith 2′-O-methyl nucleosides with the 2′-fluoro being in the evennumbered positions.

Set 3: As a variant of Set 2: To reduce any undesirable seed sequencedependent off-target effects on the part of ags-siRNA or ags-IMiRcompounds a 2′-O-methyl modification can be used for nucleoside position2. It is important for potential steric hindrance reasons that thenucleoside in position 14 in particular and to a lesser extent thenucleoside in position 16 not have a 2′-O-methyl or larger 2′-ribosemodification. Thus, when a 2′-O-methyl modification is used for thenucleoside in position 2 it is necessary that two contiguous nucleosidesin the region defined by positions 3-13 have a 2′-fluoro modified sugarso that when the alternating pattern of single 2′-O-methyl with single2′-fluoro modified sugar is continued the 2′-fluoro modification willfall on nucleoside positions 14 and 16.

Set 4: As a variant to Set 3 the nucleosides in position 14 can beribose or HM and optionally the nucleoside in position 16 can also beribose or HM.

Set 5: Phosphorothioate linkages can be added to linkage sites 2-3, andto linkage site 18-19 modified while the other modifications areaccording to Set 1, Set 2 or Set 3 when there is a phosphorothioate inlinkage site 1-2 and there is an overhang precursor where the units arelinked to each other and to nucleoside 19 by phosphorothioates.

Set 6: Additional phosphorothioate linkages can be added to thoseappearing in Set 5 in the following linkages sites (U-G, U-A, C-A, C-C,U-C, C-G, A-C and A-U) but preferably the added phosphorothioates arenot contiguous when they are in the targeting code.

Providing basic nuclease resistance to nucleoside positions 2-19 ofagsRNAi compounds to be used with or without a protective carrier can beachieved by one of the following sets of modifications:

Set 1: 2′-fluoro alternating with 2′-O-methyl nucleosides in positions2-19 with the 2′-fluoro being in the even numbered positions wherephosphorothioate linkages occur between nucleoside positions 2-3, 4-5,6-7, 8-9, 10-11, 12-13, 14-15, 15-16, 16-17, 17-18 and 18-19 withphosphodiester linkages in positions 3-4, 5-6, 7-8, 9-10, 11-12 and13-14.

Set 2: A variant of Set 1 where there is a 3 or 4 unit overhangprecursor where the units are linked by phosphorothioate linkages toeach other and to the nucleoside in position 19 then optionally thephosphorothioate linkages occur between nucleoside positions 2-3, 4-5,6-7, 8-9, 10-11, 12-13, 14-15, 16-17, 17-18 and 18-19 withphosphodiester linkages in positions 3-4, 5-6, 7-8, 9-10, 11-12, 13-14and 15-16.

Set 3: Optionally the pattern of 2′-fluoro alternating with 2′-O-methylnucleosides can be adjusted when an AGSD sugar modification replaces a2′-fluoro modified sugar. In such an instance one or both of thecontiguous 2′-O-methyl sugars can be changed to 2′-fluoro.

Set 4: To reduce any undesirable seed sequence dependent off-targeteffects on the part of ags-siRNA or ags-IMiR compounds a 2′-O-methylmodification can be used for nucleoside position 2. It is important forpotential steric hindrance reasons that the nucleoside in position 14 inparticular and to a lesser extent the nucleoside in position 16 not havea 2′-O-methyl or larger 2′-ribose modification. Thus, when a 2′-O-methylmodification is used for the nucleoside in position 2 that twocontiguous nucleosides in the region defined by positions 3-13 have a2′-fluoro modified sugar so that when the alternating pattern of single2′-O-methyl with single 2′-fluoro modified sugar is continued the2′-fluoro modification will fall on nucleoside positions 14 and 16.

Set 5: As a variant to Set 4 the nucleosides in position 14 can beribose or HM and optionally the nucleoside in position 16 can also beribose or HM.

Nuclease activity against oligo drugs can vary substantially betweenspecies and between organ/tissue/cell types. Further, manymodifications, such as the phosphorothioate linkage, can inhibit RNAiactivity depending on how many such linkages are present and where theyare located in the strand. The patterns of resistant linkage justdescribed, however, can be adjusted for use in subjects on an as neededbasis for a particular species and particular cell types. Susceptiblelinkages sites in particular organ/tissue/cell types in any subjectspecies can be determined using an established technique most notablyLC-MS (liquid chromatography combined with mass spectrometry). Anylinkage sites found to be preferentially cleaved by an endonuclease canbe made more resistant by adding a more resistant linkage and/or a moreresistant sugar modification to one or both or the nucleosides in anypreferentially cleaved linkage site. The relative resistance of thelinkages available for positions 2-19 isphosphodiester<phosphorothioate<boranophosphate<N3′ Phosphoramidate;while the relative resistance of the nucleoside sugars isribose<2′-fluoro<2′-O-methyl<AGSD sugar modifications.

Any of the ags-siRNA and ags-IMiR compounds suitable for use in subjectswithout a protective carrier can be further modified by conjugating C16(FIG. 14) to the nucleoside in position 1 or 8 counting from the 5′-endas described in Lima et al., Cell 150: 883-894, 2012 and/or Prakash etal., Nucleic Acids Res 43: 2993-3011, 2015.

E. Designing AgsRNAi Compounds 5′-End Modifications 1. 5′-End Phosphatesand Phosphate Analogs:

AgsRNAi compounds of the present invention can be manufactured with ahydroxyl, 5′-end phosphate group or a 5′-end phosphate analog on the 5′carbon of the 5′-end nucleoside sugar. FIG. 12 illustrates a 5′-endphosphate group on a ribose sugar. The nucleoside sugars promotingnuclease resistance that can be used in position 1 of an agsRNAicompound are selected from the group consisting of 2′-fluoro,2′-O-methyl, 2′-methoxyethyl, 2′-deoxyribose, LNA, FANA, 4'S-FANA, ALN,AENA, CENA, HM, HNA, EA, F-CeNA, CeNA, UNA, CRN R monomer and CRN Qmonomer.

A number of linkages that are more nuclease resistant thanphosphorothioates are provided herein. A subset of these can be used tolink nucleoside positions 1 and 2. One advantage of this is that itallows ribose or 2′-fluoro to be used in position 1 in agsRNAi compoundsthat are not administered with a protective carrier. The advantage ofhaving ribose or 2′-fluoro in position 1 is that a nucleoside with oneof these sugars and a hydroxyl on the 5′ carbon of the 5′-end nucleosidesugar is more susceptible to the addition of a 5′-end phosphate group byan intracellular kinase compared to nucleosides with one of the othersugars. The linkage between positions 1-2 suitable for this purpose canbe N3′ phosphoramidate or amide. These and other linkages suitable foruse in oligonucleotides are reviewed in Deleavy and Damha (Chemistry &Biology 19: 937-53, 2012).

The 5′-phosphate analog suitable for conjugation some of these 5′-endnucleosides is 5′-(E)-vinylphosphonate (5′-VP). It is described alongwith synthesis methods in publications that include the following: Limaet al., Cell 150: 883-894, 2012; Prakash et al., Nucleic Acids Res 43:2993-3011, 2015; WO 2011/139699; WO 2011/139702. 5′-VP is illustrated inFIG. 15 where it is conjugated to a thymidine with a 2′-methoxyethylmodification. It can be used with any of one of the nucleoside sugarchemistries provided herein where 2′-O-methyl, 2′-methoxyethyl, FANA,EA, AENA, CENA and HM are preferred.

The 5′-end nucleoside is not available to interact with the target so itcan have any of standard bases (G, C, U and A). Consequently, this basecan be selected on the basis of the base found on the nucleoside inposition 2. As a result the 5′-terminal linkage site can be designed tohave one of the 8 linkage sites that are generally more resistant tonuclease attack than the 8 other possible linkage site combinations thatcan be generated on the basis of different combinations of standardbases. Thus, depending on what base is in position 2 the base for thenucleoside in position 1 optionally can be selected from the groupconsisting of A-A, U-U, G-G, G-C, G-U, G-A, A-G and C-U.

F. Designing AgsRNAi Compounds Nucleoside Positions 2-19 1. AvoidingSteric Hindrance Problems:

Steric hindrance problems related to modifications of guide strands havebeen identified in two different ways. One of these involves summarizinga number of studies where various modifications to guide strands inparticular positions have been shown to reduce silencing activity wherethe reduction has been attributed to the modification projecting amoiety into either the major or minor grove of the duplex formed by theguide strand and the passenger strand. Even though agsRNAi compounds aretypically used without a passenger strand nevertheless modifications toguide strands that can produce these steric hindrance problems should beavoided.

With respect to sugar modifications it is clear, for example, that2′-methoxyethyl modifications in most guide strand positions in therange of positions 1-19 reduce silencing activity. The exceptions areposition 1 and any one of the positions 17-19. The 2′-O-methylmodification, however, is tolerated individually in any one of thepositions 1-19 (other than position 2 in the case of miRNA mimics suchas ags-MiRs) so the size of this modification provides a convenientapproximate limit on the size of any sugar moiety projections into thehelical grove.

The other way of identifying potential steric hindrance problems basedon moieties projecting from a modified sugar was based on noting that2′-O-methyl in position 14 substantially inhibits silencing activity inboth guide strands with siRNA and those with miRNA activity. To a lesserdegree this is also true for nucleosides in position 16. It is now clearfrom detailed studies of the interaction of the various nucleosides andlinkages in a guide strand with human AGO-2 that the nucleosides inpositions 14-18 are threaded through a narrow channel between the PAZand N domains (Schirle et al., Science 346: 608-613, 2014). Thenarrowness of this channel imposes limits on the size of the 2′modifications that can be made to the sugars of the nucleosides passingthrough this channel. This limit is set by the size of the 2′-O-methylgroup, which is approximately 23 cubic angstroms in size. So larger2′-end modifications should not be used in positions 15, 17 and 18 ofagsRNAi and smaller 2′ modifications such as fluoro, if any, should beused in positions 14 and 16.

There is less data of this type related to possible or actual sterichindrance problems generated by moieties projecting from nucleosidebases. But is clear from studies using the 5-methylcytosine base thatthe resulting projection of the methyl group into the major grove causessteric hindrance problems reflected in substantially reduced siRNAsilencing activity when the base was in nucleoside position 10, 12 or 14(Elmen et al., Nucleic Acids Res 33: 439-447, 2005). The5-methylcytosine did not cause a reduction in silencing when it was inposition 2, however. The Schirle et al. (2014) study indicates this basemodification would also be tolerated in positions 3-6, 8, 9 and 17-19.Thus, 5-methylcytosine and other bases with a 23 cubic angstrom orlarger moiety projecting from the 5 position of the base, such as theAGSD base 5-methyluracil are preferably not used in the positions where5-methylcytosine has been shown to reduce silencing activity in doublestrand RNAi triggers.

Moieties on some other bases, such as those conjugated to the C-5position of some pyrimidine bases, also can project in to the majorgroove in an A-type duplex. For use as bases in agsRNAi in nucleosidepositions where 5-methylcytosine is acceptable these moieties arepreferred to be smaller than a propynyl group. Propynl groups occupyapproximately 53 cubic angstroms of space while the 2′-O-methyl groupoccupies approximately 23 cubic angstroms of space.

These findings set limits on the size of sugar and base modificationmoieties in one or more of positions 2-19 that would project into themajor or minor groove in order to qualify them for possible use in anagsRNAi compound. More specifically, in the case of 2′ carbonaccommodating modifications to ribose or to the corresponding carbon inanother sugar it is preferred that the structure be no larger than a2′-O-methyl. Such alkyl groups project into the minor groove that isnarrower than the major groove. The exceptions to this rule include the5′-end terminal nucleoside and nucleoside(s), if any, in the overhangprecursor. Here larger 2′-modifications such as those projecting from2′-methyoxyethyl or EA can be tolerated. Another exception ismodifications to the nucleoside in the second position from the 5′-endof an ags-siRNA or ags-IMiR where a nucleoside modification of the typeprovided for herein and in the art that reduces off target effects dueto the seed region acting as a targeting code can be used.

Sugar and base modifications that promote the C3′-endo conformation inthe nucleoside in which they are found and in contiguous nucleosideswith the most flexible and/or flexible sugars and that do not causesteric hindrance problems that significantly reduce silencing activityare suitable for use as AGSD modifications in agsRNAi compounds.

The existence of substantial steric hindrance problems that woulddisqualify a particular sugar or base modification from being an AGSDmodification can be operationally identified. When present in aconventional double strand RNAi drug or trigger, AGSD moieties ormodifications do not substantially interfere with the RNAi activity ofthe drug or trigger. Substantial interference in the case of amodification to a guide strand with siRNA activity being equal to orgreater than a 20, 30, 40, 50, 60, 70 or 80% reduction in the level oftarget suppression at ED₅₀ dose seen for the cognate siRNA without thetest modification.

Substantial interference in the case of a modification to a guide strandwith miRNA activity being equal to or greater than a 20, 30, 40, 50, 60,70 or 80% reduction in the level of suppression of 1, 2, 3 or 4 targetsat ED₅₀ dose seen for the cognate miRNA without the test modification.

Since modifications to sugars and/or bases typically affect the regionalintrastrand binding affinity between passenger and guide strands theinsertion of such test modifications into the guide strand must beaccompanied by any needed modifications to the passenger strand toensure the efficient loading of the intended guide strand into RISC. Inparticular the affinities of the terminal 4 duplexed nucleosides at eachend of the RNAi trigger must be consistent with the asymmetry rule thatstates the duplexed end with the 5′-end of the passenger strand musthave a higher intrastrand affinity then the terminal duplex with the5′-end of the guide strand.

2. AGSD Sugar Modifications:

AGSD sugar modifications suitable for use in the present invention canbe any of those sugars that meet the criteria provided herein forselecting such sugars. The specific AGSD sugars provided herein for usein agsRNAi compounds in positions 2-19 are independently selected fromthe group consisting of LNA, HNA, ANA, CRN R monomer, CRN Q monomer, HM,FHNA, CeNA, F-CeNA and cEt.

AGSD sugar modifications vary in their flexibility. Flexibility is ameasure of how readily the sugar assumes a conformation other thanC3′-endo when it is a component of a nucleoside and is acted on by oneor more contiguous nucleosides linked to it by a phosphodiester orphosphorothioate linkage and where the contiguous sugar(s) prefer aconformation other than C3′-endo. Examples of nucleotide sugars thatprefer other conformations are 2′-deoxyribose and FANA.

When considering sugar conformations and the effects of continuousnucleoside sugars it is assumed the sugar in question is in a nucleosidethat is linked to other nucleosides in a single stranded structure thatis in solution under physiologic salt and pH conditions. The lessflexible the AGSD sugar the less likely its conformation is to beaffected by contiguous nucleosides but the more likely it is toinfluence the conformation of contiguous nucleosides with equallyflexible or less flexible sugars.

Table 1 ranks semi-quantitatively by their flexibility those non-AGSDand AGSD sugar modifications specifically provided for herein for use inagsRNAi. The sugars are assumed to be part of a nucleoside that islinked to other nucleosides and evaluated under the conditions as justdiscussed. As the table shows, the non-AGSD sugars are the most flexibleand, therefore, are the most susceptible of the listed sugars to havingthe probability that their sugar will be in the C3′-endo conformationincreased by the presence of a contiguous nucleoside with an AGSD sugar.

In addition, the likelihood that one of the non-AGSD sugars will be in aC3′-endo conformation and the ease with which it responds to theinfluence of contiguous nucleosides will depend on whether it has apurine or a pyrimidine base. Nucleosides with one of these non-AGSDsugars and a purine base will be less likely to have their sugar in aC3′-endo conformation compared to a nucleoside with a pyrimidine baseand the former will be less likely to be influenced by a contiguousnucleoside with a AGSD modification.

The resistance of the more flexible sugar in a nucleoside with a purinebase to the influence of contiguous nucleosides increases whennucleosides with more flexible sugars and purine bases occur in purinerich regions. For example, a purine rich region in a strand with aconcentration of purine nucleosides such as -AAUA- or -AACA-, canpromote more of a B-type that is characterized by a C2′-endo sugarconformation or an unstacked local area in a helix rather than theA-type that is characterized by the C3′-endo sugar conformation that ispreferred when the bases are pyrimidines.

As the flexibility of the sugar in a given nucleoside decreases the morelikely it is to be in the C3′-endo conformation and the more likely itis to influence the conformation of equally or more flexible sugars incontiguous nucleosides. The two sugars, LNA and cET, with a rigidC3′-endo conformation, however, are not susceptible to the influence ofcontiguous nucleosides.

TABLE 1 Ranking of AGSD and Non-AGSD Sugars by Flexibility and by theRelative Effect of a Nucleoside Containing a Particular Sugar on theConformation of the Same or Contiguous Nucleoside(s) Examples of AGSDSugars Flexible Non-AGSD HNA Sugars FHNA Semi-Flexible Most Flexible ANACRN 2′-Fluoro CeNA (R monomer) Rigid 2′-O-Methyl F-CeNA CRN LNAConditions Ribose HM (Q monomer) cEt Susceptibility of the Purine ++ + −Indicated Sugar to Base ++ having its to +++ Conformation PyrimidineInfluenced by a Less Base ++++ Flexible Sugar in a Contiguous NucleosideEffectiveness of N/A ++ +++ ++++ Particular AGSD Sugars in Affecting theConformation of more flexible Sugars Appearing in Contiguous NucleosidesProbability the N/A +++ ++++ +++++ AGSD Sugar will Assume a C3′-endoConformation When Part of a Nucleoside

These general considerations make it clear that the minimum frequency ofAGSD sugar modifications needed to promote the activity, potency andduration of effect of agsRNAi over the ssRNAi known in the art will bebased on a number of factors including the flexibility of the AGSD sugarand the flexibility of the contiguous sugars which will depend onwhether they have purine or pyrimidine bases. It is also important tonote that at most the influence of a AGSD sugar on contiguous moreflexible sugars will extend about 3 nucleoside positions in one or bothdirections (i.e. upstream or downstream).

With respect to the density of AGSD sugar modifications it is importantto note that AGSD sugars do not exactly match native ribose in aC3′-endo conformation. Since such deviations are multiplied when theyappear in multiple contiguous nucleosides it is important to set upperlimits on the frequency of these modifications in an agsRNAi strand.

The rules for applying AGSD sugar modifications to positions 2-19 ofagsRNAi compounds are as follows:

-   -   1) AGSD sugar modifications to the seed sequence nucleosides of        ags-MiRs that have the seed sequence as their targeting code are        optional.    -   2) It is preferred that the sugar in position 2 of an ags-siRNA        or an ags-IMiR be a 2′-O-methyl.    -   3) It is preferred that the sugar in position 2 of an ags-MiR be        2′-fluoro, ribose or HM.    -   4) In a purine rich region it is preferred that there be at        least one nucleoside with an AGSD sugar modification per 3        nucleosides with a purine base.    -   5) It is preferred that there be no more than 5 contiguous        nucleosides with a pyrimidine base without at least one        nucleoside with an AGSD sugar and/or AGSD base.    -   6) It is preferred that there be at least one nucleoside with a        non-AGSD sugar be between nucleosides with AGSD sugars.    -   7) It is preferred that there be at least 4 nucleosides with an        AGSD sugar among nucleosides 2-19 and that at least 2 of these        be in the 5′-end half of an ags-siRNA or an ags-IMiR and 2 in        the 3′-end half    -   8) It is preferred that at least 2 nucleosides with an AGSD        sugar be included in the 3′-end half of an ags-MiR where        position 10 is considered to be in the 3′-end half.

3. AGSD Base Modifications:

AGSD base modifications suitable for use in the present invention can beany of those bases that meet the criteria provided herein for selectingsuch bases. The specific AGSD bases provided herein for use in agsRNAicompounds are independently selected from the group consisting of2-thiouracil (U), 4-thiouracil (C), pseudouracil (U) and 5-methyluracil(U). The letter in parenthesis after the name of the base indicateswhich standard base the AGSD base substitutes for.

When pseudouracil is used in a nucleoside its ability to promote aC3′-endo conformation in a contiguous nucleoside with a more flexible orflexible sugars shown in Table 1 is asymmetric. It has a more potenteffect on the sugar conformation of upstream nucleosides than on thedownstream ones, for example, it can affect the sugar conformation in 2or 3 upstream purine nucleosides with flexible sugars while onlyaffecting one down stream purine nucleoside with a flexible sugar.

The rules for applying AGSD sugar modifications to positions 2-19 ofagsRNAi compounds are as follows:

-   -   1) AGSD bases can be used in the same nucleoside with any of the        non-AGSD and AGSD sugars provided herein.    -   2) It is preferred that there be at least one nucleoside with an        AGSD base in any region having at least 5 consecutive        pyrimidines containing nucleosides.    -   3) It is preferred that any purine rich region that is        interrupted by a pyrimidine containing nucleoside that that        nucleoside have an AGSD base.    -   4) 5-methyluracil is preferably not used in nucleoside positions        12, 14 or 16 of any agsRNAi and also preferably not used in        positions 10 and 11 of an ags-siRNA or ags-IMiR.

4. Reducing Off-Target Effects:

The principal off-target effects caused by RNAi triggers generally andalso by agsRNAi compounds involves either or both of the following: (1)the seed sequence of an ags-siRNA or ags-IMiR engaging targets and thuscausing an unintended miRNA mimicking effect; and/or (2) the compoundactivates an innate immune response in a subject that leads to anunacceptable level symptoms.

Off-target effects due to the seed region directing an ags-siRNA orags-IMiR to have unintended miRNA mimicking activity can be inhibited byusing one or two of the following modifications as needed: (1) a2′-O-methyl in position 2; (2) 1-3 CENA modified nucleosides inserted inthe seed sequence with inclusion of position 3 from the 5′-end of thestrand being preferred; (3) an UNA used preferably in position 7 fromthe 5′-end of the strand; and (4) replacing any adenine containingnucleoside with a modification selected from the groupN2-propyl-2-aminopurine or N2-cyclopentyl-2-aminopurine and/or areplacing a guanine containing nucleoside with a N2-cyclopentylguaninemodification where one or more of these modifications can be used inposition(s) 2 and/or 7 from the 5′-end of the strand. These basemodifications can be used with any of the sugar modifications providedherein.

Several of the modifications commonly applied to agsRNAi compounds willhave the additional effect of reducing the likelihood the compound willengender an innate immune response. Any further inhibition of an innateimmune response that might be needed can be achieved by using the2′-O-methyl modification in one or more uracil, adenine or guaninecontaining nucleosides. It is preferred, however, that a 2′-O-methyl notbe used in positions 14 or 16 in any agsRNAi compound and that it not beused in position 2 in an ags-MiR. 5-methylcytosine can also be used, asneeded, to reduce innate immune responses but 5-methyluracil ispreferably not used in nucleoside positions 12, 14 or 16 of any agsRNAiand also preferably not used in positions 10 and 11 of an ags-siRNA orags-IMiR.

Off-target effects due to AGO-2 based catalytic silencing activity onthe part of an ags-MiR with a seed sequence targeting code can beinhibited by replacing the nucleosides in positions 10 and/or 11 withone or two mismatches with the unintended target and/or replacing themwith modified nucleosides with a base or sugar modification selectedfrom the group 2,4-dichlorobenzene, 3-methyluracil, UNA,5,6-dihydrouracil and N⁴,N⁴-dimethylcytosine. The modified bases can beused with any of the sugars or sugar substitutes provided herein.Alternatively, the modular approach can be used to generate an ags-MiRwith the required 5′-end module along with a seed vehicle that does notrecognize the unintended target.

G. Designing Ags-MiR Compounds Using the Modular Approach 1. Overview:

In addition to modifying endogenous miRNA guide strands to generateags-MiRs, ags-MiRs based on a seed sequence targeting code can beconstructed by applying basic nuclease resistance, AGSD and othermodifications provided herein to modular components that can be combinedto form the active compound. This approach can increase the speed bywhich highly active ags-MiRs can be generated and can improve thesilencing activity on the desired targets compared to ags-MiRs based onthe entire sequence of any endogenous miRNA guide strand to be mimicked.The seed sequence used in an ags-MiR can be taken from an endogenousmiRNA or be a novel sequence selected for its ability to direct thesilencing a particular mRNA or set of mRNAs.

Moving in the 5′ to 3′ direction the modules are the following: (1) the5′-end module that consists of the first 8 or 9 consecutive nucleosidesand, therefore, includes the seed sequence; (2) the seed vehicle thatincludes the next 10 or 11 nucleosides depending on the length of the5′-end module to bring the total length exclusive of any overhangprecursor to 19; and (3) the overhang precursor if any.

2. 5′-End Module:

MiRbase (www.mirbase.org) provides the sequences for the 5′-end 8 or 9nucleosides for endogenous human miRNAs that will be used to generateags-MiR mimics of a particular naturally occurring miRNA. The base forthe nucleoside in position 1, however, can be any of the standard basesprovided herein (A, G, C, U and T). This nucleoside will be modified inaccordance with the rules stated in the section entitled “DesigningAgsRNAi Compounds: 5′-End Modifications.”

The rest of the nucleosides in the 5′-end module are then modified inaccordance with one set of the rules for providing basic nucleaseresistance. AGSD modifications are then added but are optional for theseed sequence. The reason these modifications are optional in the seedsequence is that AGSD modifications increase the binding affinity of theseed sequence for their target and thereby can increase the silencingactivity. Thus, the use of AGSD modifications to this region or not willdepend on the outcomes the ags-MiR is intended to achieve with respectto target suppression levels.

Table 2 provides a list of modifications that can be made to seedsequence nucleosides in order to increase their binding affinity withtheir targets. These include some non-AGSD and some AGSD modifications.

TABLE 2 EXAMPLES OF NUCLEOSIDE MODIFICATIONS SUITABLE FOR USE IN THESEED SEQUENCES OF ags-MiR COMPOUNDS TO INCREASE THEIR BINDING AFFINITYWITH THEIR TARGETS Degrees Change in Tm per Modifi- Modification cationComments 2′-fluoro plus 1.0- plus 2.0 2′-O-methyl plus 0.5- plus 1.0 LNAplus 2.0- LNA with adenine has about one-half of plus 9.0 thestabilizing effect of LNAs with other standard bases. Using2,6-diaminopurine or replacing a complementary uracil containingnucleoside with an LNA with a thymine base can reverse this. Using a 2-thiothymine replacement for a thymine can increase the affinity of a LNAbringing it to the upper end of the indicated Tm range. 2,6- plus 1.0-Replacement of adenine with 2,6- diaminopurine plus 3.5 diaminopurineincreases the Tm. It can be paired with any of the sugar modificationsor substitutes provided for herein to form a nucleoside. Thecomplementary partner nucleoside can have uracil or thymine.2-thiouracil plus 1.0- The complimentary nucleoside in the plus 3.0target strand must contain adenine rather than guanine when the goal isto optimize stability. The most stabilizing nucleosides have2-thiouridine paired with LNA where the use of this base furtherincreases the stabilizing effect of LNA. 4-thiouracil plus 3.0-4-thiouracil can be paired with any of the plus 6.0 sugar modificationsor sugar substitutes provided for herein to form a nucleoside. Thecomplimentary nucleoside in the partner strand must contain guaninerather than adenine when the goal is to increase stability particularlyrelative to a U:G wobble base. The most stabilizing nucleosides have4-thiouracil paired with LNA where the use of this base furtherincreases the stabilizing effect of the LNA modification. 5- plus 1.0methylcytosine Pseudouracil plus 1.0- plus 2.0 2-thiothymine plus 2.0-2-thiothymine can be paired with any of plus 6.0 the sugar modificationsor sugar substitutes provided for herein to form a nucleoside. The moststabilizing nucleosides have 2- thiothymine paired with LNA where theuse of this base further increases the stabilizing effect of LNA.

3. Seed Vehicle:

Any given seed vehicle sequence can be used with any given 5′-end moduleand these used with any overhang precursor that is provided herein. Inprinciple a seed vehicle can have any nucleotide sequence but certainsequences and particular sets of AGSD modification to its nucleosidesare more effective at promoting the activity, potency and/or duration ofeffect of the ags-MiR containing it than other seed vehicle sequencesand sets of AGSD modification. Thus, it is important to use optimizedseed vehicles for the production of ags-MiR compounds based on themodular approach.

Particular seed vehicle sequence are modified according to one of thesets of rules for providing basic nuclease resistance and then modifiedaccording to AGSD using the rules set out for nucleosides in positions2-19. Thirty examples of unmodified 11-mer seed vehicle sequences areprovided in Table 3 and examples of how seed vehicle sequence number 13can be modified are provided in Table 4. Here basic nuclease resistancerules applied to the seed vehicle are suitable for an ags-MiR suitablefor use with or without a protective carrier. Examples of 7 modified10-mer seed vehicle sequences are provided in Table 19.

TABLE 3 EXAMPLES OF 11-mer SEED VEHICLE SEQUENCES Sequence Sequence* SeqID Number 5′-3′ No. 1 GUUCUUUCUUU 2 AGCUUCUUCUU 3 GGUCUUAUUUG 4GGUGUUCAUUU 5 UUCUUUCUUUU 6 GCGCUUCUCUU 7 UUUUUUCUCUU 8 GUUUUCUUUCU 9GUUCUCUUCUC 10 CUUUUGUUCUC 11 CUUCUUCUUUC 12 GUUCUUGUUUC 13 CGGUUUCGUUU14 GCGCCUUUCUU 15 GUCCUUGCUUC 16 CUUCCUUCUUC 17 GCCUCUUUUCC 18GCGUUCCUUCU 19 GGGUCGUUUUU 20 GCGCCGAUUUU 21 GCUCCCUUUCU 22 AGUCUUUUCUU23 AGGCUUUCUUU 24 GCGCUCUCUUC 25 GUUUCGUUCGA 26 GUUGCGUUCUA 27GUUCUCGUCUC 28 GGCCGACCUAC 29 GUCCCUUCUUC 30 GCCCUCCCUGA

Any of the nucleosides in Table 4 with an L modification(s) found in oneor more of positions 9-19 (based on full length ags-MiR) can have anygiven L or set of Ls replaced with any of those sugars provided forherein for positions 2-19 including one or more of them beingindependently selected from the group consisting of: S, J, W, V, Q, Y,O, T and cet (i.e., if multiple Ls are replaced the selectedreplacements do not all have to be the same sugar). The key for themodifications is found in the section just before Table 6 that isentitled: “Nucleoside and Linkage Modification Key for Examples ofagsRNAi Compounds Found in Tables 6-21.”

TABLE 4 EXAMPLES OF MODIFIED 11-mer SEED VEHICLE NUMBER 1~C_(M4)G_(F)~G_(M)U_(F3)~U_(M)U_(F)~C_(M)G_(F)~U_(M)~U_(F3)~U_(M)~C_(M)G_(F)~G_(M)U_(F)~U_(M3)U_(F)~C_(M)G_(F)~U_(M3)~U_(F)~U_(M3)~C_(M)G_(F)~G_(M)U_(F3)~U_(M3)U_(F)~C_(M)G_(F)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(M)U_(F3)~U_(M)U_(F)~C_(M4)G_(F)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(M)U_(F12)~U_(M)U_(F)~C_(M)G_(F)~U_(M)~U_(F12)~U_(M)~C_(M)G_(F)~G_(M)U_(F)~U_(M12)U_(F)~C_(M)G_(F)~U_(M12)~U_(F)~U_(M12)~C_(M)G_(F)~G_(M)U_(F12)~U_(M12)U_(F)~C_(M)G_(F)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(M)U_(F12)~U_(M)U_(F)~C_(M4)G_(F)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(M)U_(F)~U_(M)U_(F)~C_(M)G_(F)~U_(M)~U_(F18)~U_(M)~C_(M)G_(F)~G_(M)U_(F)~U_(M18)U_(F)~C_(M)G_(F)~U_(M18)~U_(F)~U_(M18)~C_(M)G_(F)~G_(M)U_(F)~U_(M18)U_(F)~C_(M)G_(F)~U_(M18)~U_(F18)~U_(M)~C_(M4)G_(F)~G_(M)U_(F)~U_(M)U_(F)~C_(M4)G_(F)~U_(M18)~U_(F18)~U_(M)~C_(M4)G_(F)~G_(M)U_(F3)~U_(M)U~C_(M)G_(F)~U_(M)~U_(F3)~U_(M)~C_(M)G_(F)~G_(M)U_(F)~U_(M3)U~C_(M)G_(F)~U_(M3)~U_(F)~U_(M3)~C_(M)G_(F)~G_(M)U_(F3)~U_(M3)U~C_(M)G_(F)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(M)U_(F3)~U_(M)U~C_(M4)G_(F)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(M)U_(F12)~U_(M)U~C_(M)G_(F)~U_(M)~U_(F12)~U_(M)~C_(M)G_(F)~G_(M)U_(F)~U_(M12)U~C_(M)G_(F)~U_(M12)~U_(F)~U_(M12)~C_(M)G_(F)~G_(M)U_(F12)~U_(M12)U~C_(M)G_(F)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(M)U_(F12)~U_(M)U~C_(M4)G_(F)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(M)U_(F)~U_(M)U~C_(M)G_(F)~U_(M)~U_(F18)~U_(M)~C_(M)G_(F)~G_(M)U_(F)~U_(M18)U~C_(M)G_(F)~U_(M18)~U_(F)~U_(M18)~C_(M)G_(F)~G_(M)U_(F)~U_(M18)U~C_(M)G_(F)~U_(M18)~U_(F18)~U_(M)~C_(M4)G_(F)~G_(M)U_(F)~U_(M)U~C_(M4)G_(F)~U_(M18)~U_(F18)~U_(M)C_(M)G_(L)G_(M)U_(F)U_(M)U_(F)C_(M)G_(L)U_(M)U_(F)U_(M)C_(M)G_(L)G_(M)U_(F)U_(M)UC_(M)G_(L)U_(M)U_(F)U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(M)U_(F)~C_(M)G_(L)~U_(M)~U_(F3)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(M3)U_(F)~C_(M)G_(L)~U_(M3)~U_(F)~U_(M3)~C_(M)G_(L)~G_(M)U_(F3)~U_(M3)U_(F)~C_(M)G_(L)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(M)U_(F)~C_(M4)G_(L)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(M)U_(F)~C_(M)G_(L)~U_(M)~U_(F12)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(M12)U_(F)~C_(M)G_(L)~U_(M12)~U_(F)~U_(M12)~C_(M)G_(L)~G_(M)U_(F12)~U_(M12)U_(F)~C_(M)G_(L)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(M)U_(F)~C_(M4)G_(L)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(M)U_(F)~C_(M)G_(L)~U_(M)~U_(F18)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(M18)U_(F)~C_(M)G_(L)~U_(M18)~U_(F)~U_(M18)~C_(M)G_(L)~G_(M)U_(F)~U_(M18)U_(F)~C_(M)G_(L)~U_(M18)~U_(F18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(M)U_(F)~C_(M4)G_(L)~U_(M18)~U_(F18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(M)U~C_(M)G_(L)~U_(M)~U_(F3)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(M3)U~C_(M)G_(L)~U_(M3)~U_(F)~U_(M3)~C_(M)G_(L)~G_(M)U_(F3)~U_(M3)U~C_(M)G_(L)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(M)U~C_(M4)G_(L)~U_(M3)~U_(F3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(M)U~C_(M)G_(L)~U_(M)~U_(F12)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(M12)U~C_(M)G_(L)~U_(M12)~U_(F)~U_(M12)~C_(M)G_(L)~G_(M)U_(F12)~U_(M12)U~C_(M)G_(L)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(M)U~C_(M4)G_(L)~U_(M12)~U_(F12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(M)U~C_(M)G_(L)~U_(M)~U_(F18)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(M18)U~C_(M)G_(L)~U_(M18)~U_(F)~U_(M18)~C_(M)G_(L)~G_(M)U_(F)~U_(M18)U~C_(M)G_(L)~U_(M18)~U_(F18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(M)U~C_(M4)G_(L)~U_(M18)~U_(F18)~U_(M)C_(M)G_(F)G_(L)U_(F)U_(M)U_(F)C_(L)G_(F)U_(L)U_(F)U_(M)C_(M)G_(F)G_(L)U_(F)U_(M)UC_(L)G_(F)U_(L)U_(F)U_(M)~C_(M4)G_(F)~G_(L)U_(F3)~U_(M)U_(F)~C_(L)G_(F)~U_(L)~U_(F3)~U_(M)~C_(M)G_(F)~G_(L)U_(F)~U_(M3)U_(F)~C_(L)G_(F)~U_(L3)~U_(F)~U_(M3)~C_(M)G_(F)~G_(L)U_(F3)~U_(M3)U_(F)~C_(L)G_(F)~U_(L3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(L)U_(F3)~U_(M)U_(F)~C_(L4)G_(F)~U_(L3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(L)U_(F12)~U_(M)U_(F)~C_(L)G_(F)~U_(L)~U_(F12)~U_(M)~C_(M)G_(F)~G_(L)U_(F)~U_(M12)U_(F)~C_(L)G_(F)~U_(L12)~U_(F)~U_(M12)~C_(M)G_(F)~G_(L)U_(F12)~U_(M12)U_(F)~C_(L)G_(F)~U_(L12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(L)U_(F12)~U_(M)U_(F)~C_(L4)G_(F)~U_(L12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(L)U_(F)~U_(M)U_(F)~C_(L)G_(F)~U_(L)~U_(F18)~U_(M)~C_(M)G_(F)~G_(L)U_(F)~U_(M18)U_(F)~C_(L)G_(F)~U_(L18)~U_(F)~U_(M18)~C_(M)G_(F)~G_(L)U_(F)~U_(M18)U_(F)~C_(L)G_(F)~U_(L18)~U_(F18)~U_(M)~C_(M4)G_(F)~G_(L)U_(F)~U_(M)U_(F)~C_(L4)G_(F)~U_(L18)~U_(F18)~U_(M)~C_(M4)G_(F)~G_(L)U_(F3)~U_(M)U~C_(L)G_(F)~U_(L)~U_(F3)~U_(M)~C_(M)G_(F)~G_(L)U_(F)~U_(M3)U~C_(L)G_(F)~U_(L3)~U_(F)~U_(M3)~C_(M)G_(F)~G_(L)U_(F3)~U_(M3)U~C_(L)G_(F)~U_(L3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(L)U_(F3)~U_(M)U~C_(L4)G_(F)~U_(L3)~U_(F3)~U_(M)~C_(M4)G_(F)~G_(L)U_(F12)~U_(M)U~C_(L)G_(F)~U_(L)~U_(F12)~U_(M)~C_(M)G_(F)~G_(L)U_(F)~U_(M12)U~C_(L)G_(F)~U_(L12)~U_(F)~U_(M12)~C_(M)G_(F)~G_(L)U_(F12)~U_(M12)U~C_(L)G_(F)~U_(L12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(L)U_(F12)~U_(M)U~C_(L4)G_(F)~U_(L12)~U_(F12)~U_(M)~C_(M4)G_(F)~G_(L)U_(F)~U_(M)U~C_(L)G_(F)~U_(L)~U_(F18)~U_(M)~C_(M)G_(F)~G_(L)U_(F)~U_(M18)U~C_(L)G_(F)~U_(L18)~U_(F)~U_(M18)~C_(M)G_(F)~G_(L)U_(F)~U_(M18)U~C_(L)G_(F)~U_(L18)~U_(F18)~U_(M)~C_(M4)G_(F)~G_(L)U_(F)~U_(M)U~C_(L4)G_(F)~U_(L18)~U_(F18)~U_(M)C_(M)G_(L)G_(M)U_(F)U_(L)U_(F)C_(M)G_(F)U_(M)U_(L)U_(M)C_(M)G_(L)G_(M)U_(F)U_(L)UC_(M)G_(F)U_(M)U_(L)U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U_(F)~C_(M)G_(F)~U_(M)~U_(L3)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L3)U_(F)~C_(M)G_(F)~U_(M3)~U_(L)~U_(M3)~C_(M)G_(L)~G_(M)U_(F3)~U_(L3)U_(F)~C_(M)G_(F)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U_(F)~C_(M4)G_(F)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U_(F)~C_(M)G_(F)~U_(M)~U_(L12)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L12)U_(F)~C_(M)G_(F)~U_(M12)~U_(L)~U_(M12)~C_(M)G_(L)~G_(M)U_(F12)~U_(L12)U_(F)~C_(M)G_(F)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U_(F)~C_(M4)G_(F)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U_(F)~C_(M)G_(F)~U_(M)~U_(L18)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U_(F)~C_(M)G_(F)~U_(M18)~U_(L)~U_(M18)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U_(F)~C_(M)G_(F)~U_(M18)~U_(L18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U_(F)~C_(M4)G_(F)~U_(M18)~U_(L18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U~C_(M)G_(F)~U_(M)~U_(L3)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L3)U~C_(M)G_(F)~U_(M3)~U_(L)~U_(M3)~C_(M)G_(L)~G_(M)U_(F3)~U_(L3)U~C_(M)G_(F)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U~C_(M4)G_(F)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U~C_(M)G_(F)~U_(M)~U_(L12)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L12)U~C_(M)G_(F)~U_(M12)~U_(L)~U_(M12)~C_(M)G_(L)~G_(M)U_(F12)~U_(L12)U~C_(M)G_(F)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U~C_(M4)G_(F)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U~C_(M)G_(F)~U_(M)~U_(L18)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U~C_(M)G_(F)~U_(M18)~U_(L)~U_(M18)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U~C_(M)G_(F)~U_(M18)~U_(L18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U~C_(M4)G_(F)~U_(M18)~U_(L18)~U_(M)C_(L)G_(F)G_(M)U_(L)U_(M)U_(F)C_(M)G_(F)U_(L)U_(F)U_(L)C_(L)G_(F)G_(M)U_(L)U_(M)UC_(M)G_(F)U_(L)U_(F)U_(L)~C_(L4)G_(F)~G_(M)U_(L3)~U_(M)U_(F)~C_(M)G_(F)~U_(L)~U_(F3)~U_(L)~C_(L)G_(F)~G_(M)U_(L)~U_(M3)U_(F)~C_(M)G_(F)~U_(L3)~U_(F)~U_(L3)~C_(L)G_(F)~G_(M)U_(L3)~U_(M3)U_(F)~C_(M)G_(F)~U_(L3)~U_(F3)~U_(L)~C_(L4)G_(F)~G_(M)U_(L3)~U_(M)U_(F)~C_(M4)G_(F)~U_(L3)~U_(F3)~U_(L)~C_(L4)G_(F)~G_(M)U_(L12)~U_(M)U_(F)~C_(M)G_(F)~U_(L)~U_(F12)~U_(L)~C_(L)G_(F)~G_(M)U_(L)~U_(M12)U_(F)~C_(M)G_(F)~U_(L12)~U_(F)~U_(L12)~C_(L)G_(F)~G_(M)U_(L12)~U_(M12)U_(F)~C_(M)G_(F)~U_(L12)~U_(F12)~U_(L)~C_(L4)G_(F)~G_(M)U_(L12)~U_(M)U_(F)~C_(M4)G_(F)~U_(L12)~U_(F12)~U_(L)~C_(L4)G_(F)~G_(M)U_(L)~U_(M)U_(F)~C_(M)G_(F)~U_(L)~U_(F18)~U_(L)~C_(L)G_(F)~G_(M)U_(L)~U_(M18)U_(F)~C_(M)G_(F)~U_(L18)~U_(F)~U_(L18)~C_(L)G_(F)~G_(M)U_(L)~U_(M18)U_(F)~C_(M)G_(F)~U_(L18)~U_(F18)~U_(L)~C_(L4)G_(F)~G_(M)U_(L)~U_(M)U_(F)~C_(M4)G_(F)~U_(L18)~U_(F18)~U_(L)~C_(L4)G_(F)~G_(M)U_(L3)~U_(M)U~C_(M)G_(F)~U_(L)~U_(F3)~U_(L)~C_(L)G_(F)~G_(M)U_(L)~U_(M3)U~C_(M)G_(F)~U_(L3)~U_(F)~U_(L3)~C_(L)G_(F)~G_(M)U_(L3)~U_(M3)U~C_(M)G_(F)~U_(L3)~U_(F3)~U_(L)~C_(L4)G_(F)~G_(M)U_(L3)~U_(M)U~C_(M4)G_(F)~U_(L3)~U_(F3)~U_(L)~C_(L4)G_(F)~G_(M)U_(L12)~U_(M)U~C_(M)G_(F)~U_(L)~U_(F12)~U_(L)~C_(L)G_(F)~G_(M)U_(L)~U_(M12)U~C_(M)G_(F)~U_(L12)~U_(F)~U_(L12)~C_(L)G_(F)~G_(M)U_(L12)~U_(M12)U~C_(M)G_(F)~U_(L12)~U_(F12)~U_(L)~C_(L4)G_(F)~G_(M)U_(L12)~U_(M)U~C_(M4)G_(F)~U_(L12)~U_(F12)~U_(L)~C_(L4)G_(F)~G_(M)U_(L)~U_(M)U~C_(M)G_(F)~U_(L)~U_(F18)~U_(L)~C_(L)G_(F)~G_(M)U_(L)~U_(M18)U~C_(M)G_(F)~U_(L18)~U_(F)~U_(L18)~C_(L)G_(F)~G_(M)U_(L)~U_(M18)U~C_(M)G_(F)~U_(L18)~U_(F18)~U_(L)~C_(L4)G_(F)~G_(M)U_(L)~U_(M)U~C_(M4)G_(F)~U_(L18)~U_(F18)~U_(L)C_(M)G_(L)G_(M)U_(F)U_(L)U_(F)C_(M)G_(L)U_(M)U_(L)U_(M)C_(M)G_(L)G_(M)U_(F)U_(L)UC_(M)G_(L)U_(M)U_(L)U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U_(F)~C_(M)G_(L)~U_(M)~U_(L3)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L3)U_(F)~C_(M)G_(L)~U_(M3)~U_(L)~U_(M3)~C_(M)G_(L)~G_(M)U_(F3)~U_(L3)U_(F)~C_(M)G_(L)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U_(F)~C_(M4)G_(L)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U_(F)~C_(M)G_(L)~U_(M)~U_(L12)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L12)U_(F)~C_(M)G_(L)~U_(M12)~U_(L)~U_(M12)~C_(M)G_(L)~G_(M)U_(F12)~U_(L12)U_(F)~C_(M)G_(L)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U_(F)~C_(M4)G_(L)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U_(F)~C_(M)G_(L)~U_(M)~U_(L18)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U_(F)~C_(M)G_(L)~U_(M18)~U_(L)~U_(M18)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U_(F)~C_(M)G_(L)~U_(M18)~U_(L18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U_(F)~C_(M4)G_(L)~U_(M18)~U_(L18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U~C_(M)G_(L)~U_(M)~U_(L3)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L3)U~C_(M)G_(L)~U_(M3)~U_(L)~U_(M3)~C_(M)G_(L)~G_(M)U_(F3)~U_(L3)U~C_(M)G_(L)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F3)~U_(L)U~C_(M4)G_(L)~U_(M3)~U_(L3)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U~C_(M)G_(L)~U_(M)~U_(L12)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L12)U~C_(M)G_(L)~U_(M12)~U_(L)~U_(M12)~C_(M)G_(L)~G_(M)U_(F12)~U_(L12)U~C_(M)G_(L)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F12)~U_(L)U~C_(M4)G_(L)~U_(M12)~U_(L12)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U~C_(M)G_(L)~U_(M)~U_(L18)~U_(M)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U~C_(M)G_(L)~U_(M18)~U_(L)~U_(M18)~C_(M)G_(L)~G_(M)U_(F)~U_(L18)U~C_(M)G_(L)~U_(M18)~U_(L18)~U_(M)~C_(M4)G_(L)~G_(M)U_(F)~U_(L)U~C_(M4)G_(L)~U_(M18)~U_(L18)~U_(M)

H. Designing AgsRNAi Compounds Overhang Precursors

A wide range of overhang structures have been described for use at the3′-end of passenger and/or guide strands of double strand RNAi triggers.Most often they comprise nucleosides with one of the commonly used bases(A, G, U, T, C) combined with one of the commonly used sugars (ribose,2′-fluoro, 2′-O-methyl and 2′-methoxyethyl) and joined by aphosphodiester or phosphorothioate linkages. Usually they are 2nucleosides in length. In addition, more nuclease resistant linkageshave been used to link both nucleoside and certain non-nucleosidestructures to generate overhangs suitable for use in double strand RNAitriggers. Since the linked structures are not necessarily nucleosidesthe term “unit” is used generally herein to refer to the linkedstructures in overhang precursors.

In principle any of these overhangs that are suitable for use in theguide strands of double strand RNAi triggers can be used as overhangprecursors for agsRNAi but those with higher affinity for the PAZ domainof dicer and the argonaute proteins are preferred. In addition, threenucleoside long overhangs are preferred in agsRNAi compounds.

When nucleosides with bases capable of base pairing with the commonlyused based appear in overhang precursors it is important to check to seeif they promote a thermodynamically stable hairpin (50% or greater ofthe agsRNAi in the hairpin conformation under physiologic salt, pH andoligo concentration in the 10 nM or less range) in the agsRNAi. If sucha hairpin is formed then a different sequence for the overhangnucleosides is selected.

Table 5 provides examples of 3 nucleoside long overhang precursors thatare suitable for use in agsRNAi compounds. They are shown withphosphodiester (no linkage represented) or with phosphorothioatelinkages (˜). One or more of the phosphorothioate linkages can bereplaced with one of the other nuclease resistant linkages providedherein. The subscript L after a nucleoside in the table represents thatthe nucleoside has an LNA sugar and the subscript X represents anucleoside with a ribose, 2′-fluoro, or 2′-O-methylsugar. Any of thenucleosides in Table 5 with an L modification can have the Lmodification replaced with one or two of the sugars independentlyselected from the group consisting of: F, J, W, V, Y, T, TL and I. Theuse of some of these structures as 3′-end guide strand overhangs insiRNA compounds have been described previously (Bramsen et al., NucleicAcids Res 37: 2867-81, 2009).

TABLE 5 EXAMPLES OF THREE NUCLEOSIDE LONG OVERHANG PRECURSORS FOR USE INagsRNAi COMPOUNDS Sequence 5′-3′ Sequence PhosphodiesterPhosphorothioate Number Linkages Linkages 1 G_(L)U_(L)U_(X)~G_(L)~U_(L)~U_(X) 2 U_(L)U_(L)U_(X) ~U_(L)~U_(L)~U_(X) 3C_(L)U_(L)U_(X) ~C_(L)~U_(L)~U_(X) 4 G_(L)C_(L)U_(X) ~G_(L)~C_(L)~U_(X)5 A_(L)G_(L)U_(X) ~A_(L)~G_(L)~U_(X) 6 A_(L)G_(L)C_(X)~A_(L)~G_(L)~C_(X) 7 A_(L)A_(L)A_(X) ~A_(L)~A_(L)~A_(X) 8A_(L)G_(L)A_(X) ~A_(L)~G_(L)~A_(X) 9 G_(L)A_(L)A_(X) ~G_(L)~A_(L)~A_(X)10 C_(L)G_(L)C_(X) ~C_(L)~G_(L)~C_(X) 11 G_(L)G_(L)C_(X)~G_(L)~G_(L)~C_(X) 12 G_(L)G_(L)U_(X) ~G_(L)~G_(L)~U_(X)

Numerous 3′-end overhang precursor chemistries can promote activity andincrease nuclease resistance. They can also be used in agsRNAicompounds. These include but are not limited to the following where theindicated nucleoside sugars can be used with any of the standard bases:(1) morpholino; (2) tricyclo-DNA (Ittig et al., Artif DNA, PNA & XNA 1:9, 2010); (3) ribo-difluorotoluyl (Xia et al., ACS Chem Biol 1: 176,2006); (4) 4′-thioribonucleotides (Hoshika et al., Chem Bio Chem 8:2133, 2007); (5) 2′-O-methyl-4′-thioribonucleotide (Takahashi et al.,Nucleic Acids Res 37: 1353, 2009; Matsuda, Yakugaku Zasshi 131: 285,2011); (6) altritol-nucleoside (ANA) (Fisher et al., Nucleic Acids Res35: 1064, 2007); (7) cyclohexenyl-nucleoside (CeNA) (Nauwelaerts et al.,J Am Chem Soc 129; 9340, 2007; (8) piperazine (U.S. Pat. No. 6,841,675);(9) 5-bis(aminoethyl) aminoethylcarbamoylmethyl-2′-deoxyuridine or5-bis(aminoethyl) aminoethylcarbamoylmethyl-thymidine (Masud et al.,Bioorg Med Chem Lett 21: 715, 2010); and (10) peptide nucleic acidoverhangs (Potenza et al., Int J Mol Sci 9: 299-315, 2008).

The nucleosides and some non-nucleoside units used in overhangprecursors in agsRNAi strands can be linked together and to thenucleoside in position 19 to form 3′-end overhangs using a nucleaseresistant linkage selected from the group phosphorothioate,phosphonoacetate, (PACE), thiophosphonoacetate (thio-PACE), methylboranephosphine, amide, carbamate, urea, thiourea, N3′phosphoramidate andamide. (Sheehan et al., Nucleic Acids Res 31: 4109, 2003; Krishna &Caruthers, J Amer Chem Soc 133: 9844, 2011; Iwase et al., Nucleic AcidsSymposium Series 50: 175, 2006; Iwase et al., Nucleosides NucleotidesNucleic Acids 26: 1451, 2007; Iwase et al., Nucleic Acids SymposiumSeries 53: 119, 2009; Ueno et al. Biochem Biophys Res Comm 330: 1168,2005; Kitamura et al., Bioorganic & Medicinal Chemistry 21: 4494-501,2013; Deleavy and Damha Chemistry & Biology 19: 937-53, 2012).

Further, 3′-end overhang precursors can be comprised of certainhydrophobic aromatic moieties. For example, those that are comprised ofone to three units containing two six membered rings joined byphosphodiester, or one of the other linkages just listed where theunit(s) are attached to the agsRNAi nucleoside in position 19 by thesame linkage and when multiple units are used they are also joined bythe same linkage. Two unit structures are preferred in the followingexamples. Suitable ring structures include benzene, pyridine, morpholineand piperazine (U.S. Pat. No. 6,841,675). Structures based on thebenzene and pyridine rings have been previously described for 3′-endoverhang use in conventional siRNA by Ueno et al., Bioorg Med Chem Lett18:194, 2008; Ueno et al., Bioorganic & Medicinal Chemistry 17: 1974,2009; Kitamura et al., Bioorganic & Medicinal Chemistry 21: 4494-501,2013. These units include 1,3-bis(hydroxymethyl)benzene,1,3-bis(hydroxymethyl)pyridine and 1,2-bis(hydroxymethyl)benzene. Thesework particularly well with a linkage selected from the group carbamate,urea and thiourea. These structures are also suitable for agsRNAi use asoverhang precursors.

In another example of possible non-nucleoside overhang precursors foragsRNAi include the aromatic moieties that can be biaryl units where thelinkages holding the units together and to the oligo are covalentlyattached to benzene rings where the benzene ring is further covalentlyattached to a non-bridging moiety selected from the group benzene,naphthalene, phenanthrene, and pyrene (Ueno et al., Nucleic AcidsSymposium Series 53: 27, 2009; Ueno et al., Bioorganic & MedicinalChemistry 17: 1974-81. 2009; Yoshikawa et al., Bioconjugate Chem 22: 42,2011).

In addition, the 3′-end overhangs, or lack thereof, can affect theintracellular distribution of agsRNAi. AgsRNAi compounds that diffuseinto the nucleus can be expelled from the nucleus by Exportin-5 (Exp-5).This activity of Exp-5 can be rate-limiting for silencing activity atlow doses of agsRNAi. Exp-5 binds to the first two nucleosides or unitsin any 3′-end overhang(s). Thus, agsRNAi designed with 3′-end overhangprecursors comprising nucleosides have a potential advantage overagsRNAi compounds that do not have overhang precursors because they canproduce a greater presence in the cytoplasm particularly at loweragsRNAi concentrations. For agsRNAi acting on nuclear targets, however,the lack of an overhang precursor or the presence of a non-nucleosideoverhang precursor not engaged by Exp-5 can increase the activity of thecompound by reducing its expulsion from the nucleus by Exp-5.

I. Designing AgsRNAi Compounds: Additional Nuclease ResistantLinkages 1. Boranophosphate Linkage:

Selective use of the boranophosphate linkage (See FIG. 16E) in agsRNAicompounds can be used to increase their silencing activity. Linkagesites suitable for the use of the boranophosphate linkage include thoseinvolving nucleoside positions 4-5, 5-6, 6-7, 7-8 11-12 and to linknucleosides in an overhang precursor 2-4 units in length, ie., linkagesites 19-20, 20-21, 21-22 and 22-23. The presence of at least 3boranophosphate linkages is preferred exclusive of the overhangprecursor. The boranophosphate linkages can link nucleosides suitablefor use in the region bracketed by nucleosides 2-19 and/or they can linknucleosides with a 2′-deoxyribose sugar that has been substituted forthe sugar that would otherwise be present in the absence of theboranophosphate linkage. When a 2′-deoxyribose is used that has apyrimidine base it is preferred that the base be replaced with thecorresponding AGSD base.

A solid-phase synthesis method to produce oligos with boranophosphatelinkages has recently been described, see FIGS. 17 and 18 (Uehara etal., J Organic Chem 79: 3465-72, 2014). This methodology simplifies themultiple earlier methods for incorporating the boranophosphate linkageinto oligo nucleotides and it allow for the incorporation of a widerrange of nucleoside sugars including LNA. Earlier methods includeinserting boranophosphate linkages into oligos via one or the other oftwo general methods: (1) template directed enzymatic polymerization; and(2) chemical synthesis using solid supports. Boranophosphate oligoproduction can be achieved by a variety of solid phase chemicalsynthetic schemes including methods that involve modifications to thevery commonly used approaches employing phosphoramidites orH-phosphonates in the production of phosphodiesters, phosphorothioatesand phosphorodithioates among other chemistries (Li et al., Chem Rev107: 4746, 2007). Other solid phase synthesis techniques more preciselydirected to boranophosphates have also been developed. Wada and hiscolleagues, for example, have developed what they call theboranophosphotriester method that can make use of H-phosphonateintermediates (Shimizu et al., J Org Chem 71: 4262, 2006; Kawanaka etal., Bioorg Med Chem Lett 18: 3783, 2008). This method can also beapplied to the synthesis of diastereometically pure boranophosphates(Enya et al., Bioorg Med Chem 16: 9154, 2008).

The generation of oligos with mixed linkages such as boranophosphate anda number of other linkages has been accomplished by several solid phasemethods including one involving the use ofbis(trimethylsiloxy)cyclododecyloxysilyl as the 5′-O-protecting group(Brummel and Caruthers, Tetrahedron Lett 43: 749, 2002). In anotherexample the 5′-hydroxyl is initially protected with abenzhydroxybis(trimethylsilyloxy)silyl group and then deblocked byEt₃N:HF before the next cycle (McCuen et al., J Am Chem Soc 128: 8138,2006). This method can result in a 99% coupling yield and can be appliedto the synthesis of oligos with pure boranophosphate linkages orboranophosphate mixed with phosphodiester, phosphorothioate,phosphorodithioate or methyl phosphonate linkages. FIG. 16.

The boranophosphorylating reagent 2-(4-nitrophenyl)ethyl ester ofboranophosphoramidate can be used to produce boranophosphate linkedoligoribonucleosides (Lin, Synthesis and properties of new classes ofboron-containing nucleic acids, PhD Dissertation, Duke University,Durham N.C., 2001). This reagent readily reacts with a hydroxyl group onthe nucleosides in the presence of 1H-tetrazole as a catalyst. The2-(4-nitrophenyl)ethyl group can be removed by1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) through beta-elimination,producing the corresponding nucleoside boranomonophosphates (NMPB) ingood yield.

The stereo-controlled synthesis of oligo boranophosphates can beachieved using an adaptation of the oxathiaphospholane approachoriginally developed for the stereo-controlled synthesis ofphosphorothioates (Li et al., Chem Rev 107: 4746, 2007). This methodinvolves a tricoordinate phosphorus intermediate that allows for theintroduction of a borane group. Other approaches includestereo-controlled synthesis by means of chiral indole-oxazaphosphorineor chiral oxazaphospholidine. Both of these approaches initially usedfor the stereocontrolled synthesis of phosphorothioates have beensuccessfully adapted to boranophosphates (Li et al., Chem Rev 107: 4746,2007). In yet another approach to the production of the stereocontrolledsynthesis of oligos linked by boranophosphates involves the use ofH-phosphonate intermediates (Iwamato et al., Nucleic Acids Sym Ser 53:9, 2009). The template directed enzymatic polymerization method andchemical methods have been used by Shaw and her colleagues (Shaw et al.,Nucleic Acids Symp Series 52: 655-656, 2008; Hall et al., Nucleic AcidsRes 34: 2773-81, 2006).

2. Amide Linkage:

The amide linkage (FIG. 16D) can be used in the initial 5′-end linkagesite of an agsRNAi between nucleoside positions 1 and 2 and in one ormore of the linkages between the units of the overhang precursors and/orin the linkage that joins the overhang precursor to the nucleoside inposition 19. An advantage of using this linkage in these positions isthat it increases the exonuclease resistance above what is provided bythe phosphorothioate linkage. In addition to increasing the stability ofthe agsRNAi the amide linkage will allow nucleosides to have nucleosideswith ribose or with the 2′-fluoro modification to be used in nucleosideposition 1 and/or in the 3′end terminal linkage site of an overhangprecursor. As discussed in the section dealing with the 5′-endmodifications this arrangement can promote the ability of cellularenzymes to add a phosphate group to the 5′-end of the agsRNAi lackingone and thus improve its affinity with an argonaute protein. The use ofan amide linkage in these positions of an siRNA guide strand has beenpreviously reported (Iwase et al., Nucleic Acids Symposium Series 53:119, 2009; Mutisya et al. Nucleic Acids Res 42: 6542-51, 2014).

3. N3′ Phosphoramidate Linkage: (FIG. 16C)

This linkage provides greater nuclease resistance than thephosphorothioate linkage and it promotes the C3′-endo conformation inthe nucleosides it links. For example, when used to link nucleosides ina DNA oligo it drives the sugars into the C3′endo conformation that DNAstrands do not normally have (Egli and Gryaznov, CMLS Cell Mol Life Sci57: 1440-56, 2000).

When injected into mice antisense oligos with this linkage distribute tovarious tissues in the animals where they have biologic activity(Gryaznov, Chemisty & Biodiversity 7: 477-93, 2010). This implies thatlike phosphorothioates N3′ Phosphoramidate linked oligos aresufficiently adherent to plasma proteins to inhibit their clearance fromthe plasma by the kidneys but not so adherent as to prevent them frombeing taken up in tissues.

N3′ phosphoramidate linkages can be used in place of phosphorothioateand/or phosphodiester linkages in one or more positions in agsRNAicompounds. They are particularly preferred for use in any purine richareas that might be found in an agsRNAi and are particularly preferredin seed vehicles used in the modular approach to generate ags-MiRs.

J. Methods for Administering AgsRNAi Compounds to Subjects

The methods for administering agsRNAi compounds to subjects areessentially the same as for RNAse H1 dependent antisense oligos (Butleret al., Laboratory Investigation 77: 379-88, 1997; Antisense DrugTechnology: Principles, Strategies, and Applications, 2^(nd) ed.,Stanley T. Crooke (ed.) CRC Press July 2007; Bennett and Swayze, AnnuRev Pharmacol Toxicol 50: 259-93, 2010; Yu et al., Expert Opin DrugMetab Toxicol 9: 169-82, 2013). The ideal length for antisense oligosused as therapeutics is about 20 nucleosides, with about 70% or more ofthe linkages being phosphorothioate. Consequently, antisense oligo drugsdemonstrate a high level of pharmacokinetic behavior that is consistentamong oligos with different mechanisms of action, with varioussequences, and across several species including those commonly involvedin drug development such as rodents, dogs and monkeys. This consistencyallows pharmacokinetic data to be modeled and extrapolated betweenanimals and humans.

Antisense oligos can be effectively administered by a number of routesincluding i.v., s.c., i.m., topical, inhalation, and intrathecal. Theeffect of the variations in routes of bolus systemic administration onpharmacokinetics involves changes in the rate at which the peak plasmaconcentration is achieved. The range is minutes to hours. As long as thedose does not overwhelm the ability of the plasma proteins to bind theoligo, the ultimate effect of different routes of systemicadministration on ultimate tissue uptake is modest.

When administered i.v., s.c. or i.m. single stranded oligo therapeuticsare typically administered multiple times during week one and thenweekly, biweekly or monthly to maintain the effect on the target.Subcutaneous administrations are generally preferred for both animalsand humans. In mice the oligo doses can be up to about 25 mg/kg s.c.twice daily for multiple days. In the case of humans a single s.c.administration is limited to a volume of about 1 ml and this sets alimit of about 500 mg of oligo due to the viscosity of the oligosolution. As for mice there can be multiple loading doses in humans inthe first week followed by week, biweekly or monthly maintenance doses.

In certain embodiments, (e.g., for the treatment of lung disorders, suchas pulmonary fibrosis or asthma or to allow for self administration forlocal or systemic purposes) it may desirable to deliver the oligosdescribed herein in aerosolized form. A pharmaceutical compositioncomprising at least one oligo can be administered as an aerosolformulation that contains the oligos in dissolved, suspended oremulsified form in a propellant or a mixture of solvent and propellant.The aerosolized formulation is then administered through the respiratorysystem or nasal passages.

An aerosol formulation used for nasal administration is generally anaqueous solution designed to be administered to the nasal passages asdrops or sprays. Nasal solutions are generally prepared to be similar tonasal secretions and are generally isotonic and slightly buffered tomaintain a pH of about 5.5 to about 6.5, although pH values outside ofthis range can also be used. Antimicrobial agents or preservatives canalso be included in the formulation.

An aerosol formulation for use in inhalations and inhalants is designedso that the oligos are carried into the respiratory tree of the patient.See (WO 01/82868; WO 01/82873; WO 01/82980; WO 02/05730; WO 02/05785Inhalation solutions can be administered, for example, by a nebulizerInhalations or insufflations, comprising finely powdered or liquiddrugs, are delivered to the respiratory system as a pharmaceuticalaerosol of a solution or suspension of the drug in a propellant.

An aerosol formulation generally contains a propellant to aid indisbursement of the oligos. Propellants can be liquefied gases,including halocarbons, for example, fluorocarbons such as fluorinatedchlorinated hydrocarbons, hydrochlorofluorocarbons, andhydrochlorocarbons as well as hydrocarbons and hydrocarbon ethers(Remington's Pharmaceutical Sciences 18th ed., Gennaro, A. R., ed., MackPublishing Company, Easton, Pa. (1990)).

Halocarbon propellants useful in the invention include fluorocarbonpropellants in which all hydrogens are replaced with fluorine,hydrogen-containing fluorocarbon propellants, and hydrogen-containingchlorofluorocarbon propellants. Halocarbon propellants are described inJohnson, U.S. Pat. No. 5,376,359, and Purewal et al., U.S. Pat. No.5,776,434.

Hydrocarbon propellants useful in the invention include, for example,propane, isobutane, n-butane, pentane, isopentane and neopentane. Ablend of hydrocarbons can also be used as a propellant. Etherpropellants include, for example, dimethyl ether as well as numerousother ethers.

The oligos can also be dispensed with a compressed gas. The compressedgas is generally an inert gas such as carbon dioxide, nitrous oxide ornitrogen.

An aerosol formulation of the invention can also contain more than onepropellant. For example, the aerosol formulation can contain more thanone propellant from the same class such as two or more fluorocarbons. Anaerosol formulation can also contain more than one propellant fromdifferent classes. An aerosol formulation can contain any combination oftwo or more propellants from different classes, for example, afluorohydrocarbon and a hydrocarbon.

Effective aerosol formulations can also include other components, forexample, ethanol, isopropanol, propylene glycol, as well as surfactantsor other components such as oils and detergents (Remington'sPharmaceutical Sciences, 1990; Purewal et al., U.S. Pat. No. 5,776,434).These aerosol components can serve to stabilize the formulation andlubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. A solution aerosol consists of asolution of an active ingredient such as oligos in pure propellant or asa mixture of propellant and solvent. The solvent is used to dissolve theactive ingredient and/or retard the evaporation of the propellant.Solvents useful in the invention include, for example, water, ethanoland glycols. A solution aerosol contains the active ingredient peptideand a propellant and can include any combination of solvents andpreservatives or antioxidants.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation will generally contain a suspension of aneffective amount of the oligos and a dispersing agent. Dispersing agentsuseful in the invention include, for example, sorbitan trioleate, oleylalcohol, oleic acid, lecithin and corn oil. A suspension aerosolformulation can also include lubricants and other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. Anemulsion can include, for example, an alcohol such as ethanol, asurfactant, water and propellant, as well as the active ingredient, theoligos. The surfactant can be nonionic, anionic or cationic. One exampleof an emulsion can include, for example, ethanol, surfactant, water andpropellant. Another example of an emulsion can include, for example,vegetable oil, glyceryl monostearate and propane.

Oligos may be formulated for oral delivery (Tillman et al., J Pharm Sci97: 225, 2008; Raoof et al., J Pharm Sci 93: 1431, 2004; Raoof et al.,Eur J Pharm Sci 17: 131, 2002; U.S. Pat. No. 6,747,014; US 2003/0040497;US 2003/0083286; US 2003/0124196; US 2003/0176379; US 2004/0229831; US2005/0196443; US 2007/0004668; US 2007/0249551; WO 02/092616; WO03/017940; WO 03/018134; WO 99/60012). Such formulations may incorporateone or more permeability enhancers such as sodium caprate that may beincorporated into an enteric-coated dosage form with the oligo.

There are also delivery mechanisms applicable to oligos with or withoutcarriers that can be applied to particular parts of the body such as theCNS. These include the use of convection-enhanced delivery methods suchas but not limited to intracerebral clysis (convection-enhancedmicroinfusion into the brain—Jeffrey et al., Neurosurgery 46: 683, 2000)to help deliver the cell-permeable carrier/oligo complex to the targetcells in the CNS as described in WO 2008/033285.

Drug delivery mechanisms based on the exploitation of so-calledleverage-mediated uptake mechanisms are also suitable for the practiceof this invention (Schmidt and Theopold, Bioessays 26: 1344, 2004).These mechanisms involve targeting by means of soluble adhesionmolecules (SAMs) such as tetrameric lectins, cross-linkedmembrane-anchored molecules (MARMs) around lipoproteins or bulky hingemolecules leveraging MARMs to cause a local inversion of the cellmembrane curvature and formation of an internal endosome, lysosome orphagosome. More specifically leverage-mediated uptake involves lateralclustering of MARMs by SAMs thus generating the configurational energythat can drive the reaction towards internalization of the oligocarrying complex by the cell. These compositions, methods, uses andmeans of production are provided in WO 2005/074966.

The following materials and methods are provided to facilitate thepractice of the present invention. Other approaches for synthesizing andcharacterizing the agsRNAi of the invention are known to the skilledartisan and are within the scope of the present invention. The methodsprovided here are not intended to limit the invention in any way.

Synthesis of 5′-MP and 5′-VP ss-siRNAs

ssRNA are synthesized on ABI 394 synthesizer (1-2 mmol scale) or on GEHealthcare Bioscience A{umlaut over ( )}KTA oligopilot synthesizer(40-200 mmol scale) by the phosphoramidite coupling method on anUnyLinker solid support (Guzaev and Manoharan, 2003) packed in thecolumn. A 0.1 M solution of 2′-F, 2′-O-Me, and 2′-O-MOE nucleosidephosphoramidites in anhydrous CH₃CN was used for the synthesis. The2′-O-MOE-S-methyluridine-5′-deoxy-5′-methylenephosphonate-3′-phosphoramidite,2′-O-MOE-5-methyluridine-5′-deoxy-5′-vinylphosphonate-3′-phosphoramidite,2′-O—[N-(decanoyl)-6-aminohexyl]-5-methyluridine-3′-phosphoramidite, and2′-O-[N-(hexadecanoyl)-6-aminohexyl]-5-methyluridine-3′-phosphoramiditeare dissolved in 40% anhydrousvdichloromethane in anhydrous CH₃CN (0.15M) and used for the synthesis. For the coupling step, thephosphoramidites are delivered 4- to 6-fold excess over the loading onthe solid support, and phosphoramidite condensation is carried out for10 min. A solution of 6% dichloroacetic acid in toluene is used forremoving dimethoxytrityl (DMT) group from the 5′ hydroxyl group of thenucleotide. Extended detritylation condition was used to remove the DMTgroup from the secondary hydroxyl group of the UnyLinker solid support.4,5-Dicyanoimidazole (0.7 M) in anhydrous CH₃CN was used as activatorduring coupling step. Phosphorothioate linkages are introduced using0.2M solution of phenylacetyl disulfide in 1:1 pyridine/CH3CN as sulfurtransfer reagent and treated for 3 min except for the coupling of5′-deoxy-5′methylenephosphonate and 5′-deoxy-5′-vinylphosphonatephosphoramidites. Phosphorothioate linkages are introduced using asolution of3-((dimethylaminomethylene)amino)-3H-1,2,4-dithiazole-5-thione (0.05 M,DDTT) in 1:1 pyridine/CH₃CN and a 3 min contact. Solid support-boundssRNAs are washed with CH₂Cl₂ and dried under high vacuum for 4 hr. ThessRNAs are suspended in a solution of iodotrimethylsilane and pyridinein ichloromethane (dissolve 0.75 ml iodotrimethylsilane and 0.53 mlpyridine in 28.2 ml CH₂Cl₂, use 0.5 ml per mmol of solid support) andallowed to shake at room temperature for 30 min. Reaction is quenchedwith 50% triethylamine in CH₃CN containing 1 M 2-mercaptoethanol (0.5 mlper mmol of solid support). Supernatant is decanted and the solidsupport washed with 1:1 triethylamine/CH₃CN containing 1 M2-mercaptoethanol (2 3 0.5 ml per mmol of solid support). A solution of1:1 triethylamine/CH₃CN containing 1M 2-mercaptoethanol (0.5 ml per mmolof solid support) is added and kept at room temperature for 45 min.Supernatant is decanted, and the residue aqueous ammonia (28-30 WT %)containing 1M 2-mercaptoethanol (0.75 ml per mmol of solid support) isadded and heated at 55.0 for 2 hr. The reaction mixture is allowed tocome to room temperature and kept for an additional 24 hr. The solidsupport is filtered and washed thoroughly with water. The filtrate andthe washing are combined together and then cooled in an ice bath andneutralized with glacial acetic acid. The resulting colloidal solutionis allowed to stand at −20.0 for 2-3 hr. The precipitate formed iscollected by centrifugation followed by decanting the supernatant. Theprecipitated ssRNAs are then dissolved in water and purified by highpressure liquid chromatography on a reverse phase column (WatersX-Bridge C-18 5 mm, 193 250 mm, A=5 mM tributylammonium acetate in 5%aqueous CH₃CN, B=CH₃CN, 0 to 90% B in 80 min, flow 7 ml min-1,1=260 nm).The fractions were analyzed by LC-MS, and fractions containingfull-length ssRNAs pooled together. The tributylammonium counter ionscan be exchanged with sodium ions by high-pressure liquid chromatographyon a strong anion exchange column (GE Healthcare Bioscience, Source 30Q,30 mm, 2.54 3 8 cm, A=100 mM ammonium acetate in 30% aqueous CH₃CN,B=1.5 M NaBr in A, 0%-40% of B in 60 min, flow 14 ml min-1,1=260 nm).Desalting by HPLC on a reverse-phase column can give ssRNAs in anisolated yield of 15%-30% based on the initial loading on the solidsupport. ssRNAs are characterized by ion-pair-HPLC-coupled MS analysiswith Agilent 1100 MSD system. Further details on this process areprovided in Lima et al. Cell 50:883-894 (2012).

In Vitro Potency of ss-siRNA and siRNA in Primary Hepatocytes

Liver Perfusion

Mouse liver is perfused as previously described (Graham et al., 1998;Graham et al., 2001; Berry and Friend, 1969) with minor modifications.Briefly, mice are anesthetized with an intraperitoneal injection oftribromoethanol (Avertin). Inferior vena cava is catheterized andclamped. Liver is perfused with Hank's Balanced Salt Solution (lifetechnologies) and mesenteric vessel is cut for drainage. Liver wassubsequently perfused with collagenase (Roche). Following the perfusion,liver is removed and gently massaged through sterile nylon mesh. Cellsare washed in Williams E (life technologies) containing 10% fetal calfserum, HEPES, L-glutamine and antibiotic/antimycotic. Parenchymal cellsare separated from non-parenchymal via centrifugation.

Transfection

Cells are seeded in 96 well plates at 5,000-10,000 cells/well 16 hrprior to treatment with the exception of liver hepatocytes which areimmediately plated and transfected two hours post perfusion.Transfection is performed at indicated concentrations using Opti-MEMmedium (life technologies) containing 4-6 μg/ml Lipofectamine 2000 (LifeTechnologies) for 4 hr at 37° C. Growth medium, DMEM for HeLa and MEFcell lines and Williams E for hepatocytes, is replaced and cellsincubated overnight at 37° C. in 5% CO₂. Cells are lysed 16 hr posttransfection and total RNA purified using RNeasy 3000 Bio Robot(QIAGEN). Reduction of target mRNA is determined by qRT-PCR as describedbelow. Target mRNA levels can be normalized to total RNA using RiboGreen(Life Technologies). IC₅₀ curves and values are generated using Prism 4software (GraphPad).

Electroporation of ss-siRNAs

10×ss-siRNA is diluted to 1× by liver hepatocytes at a cell density of35,000 cells/well. Cells are electroporated at 165 V and a pulse lengthof 6 ms. Cell/oligo mix is transferred to a 96-well tissue culture platecontaining Williams E media and 10% FBS and incubated 16 hr prior tolysis. RNA purification and qRT-PCR are run as described above.

In Vitro Potency of ss-siRNA and siRNA in Transfected HeLa Cells

HeLa cells are seeded in 96 well plates at 5,000-10,000 cells/well 16 hrprior to treatment with the exception of liver hepatocytes which areimmediately plated and transfected two hours post perfusion.Transfection is performed at indicated concentrations using Opti-MEMmedium (life technologies) containing 4-6 μg/ml Lipofectamine 2000 (LifeTechnologies) for 4 hr at 37° C. Growth medium, DMEM for HeLa and MEFcell lines and Williams E for hepatocytes, is replaced and cellsincubated overnight at 37° C. in 5% CO₂. Cells are lysed 16 hr posttransfection and total RNA purified using RNeasy 3000 Bio Robot(QIAGEN). Reduction of target mRNA is determined by qRT-PCR as describedherein. Target mRNA levels can be normalized to total RNA usingRiboGreen (life technologies). IC50 curves and values are generatedusing Prism 4 software (GraphPad Prism regression analysis Software).

In Vivo Activity of ss-siRNA in Mice

Animal experiments can be conducted according to American Associationfor the Accreditation of Laboratory Animal Care guidelines and will beapproved by the Animal Welfare Committee (Cold Spring HarborLaboratory's Institutional Animal Care and Use Committee guidelines).Male Balb/c mice (Charles River Laboratories), aged 6-8 weeks, aremaintained at a constant temperature of 23° C. and allowed to standardlab diet and water. Dosing solutions are prepared in phosphate-bufferedsaline, sterile filtered and quantified. Mice are dosed by singleadministration (n=4), intravenous or subcutaneous, injection with theexception of subcutaneous doses above 50 mg/kg which consisted ofsubdivided injections of 25 mg/kg twice a day for indicated number ofdays. Mice are sacrificed 48 hr post treatment. Animals are anesthetizedwith isoflurane and terminal bleed performed. Immediately followingterminal blood draw, mice are sacrificed by cervical dislocation whileunder anesthesia. Liver, kidney, and spleen weights are taken and livertissue homogenized in guanidine isothiocyanate (life technologies)containing 8% β-mercaptoethanol (Sigma) immediately following thesacrifice. Liver homogenate is loaded onto Purelink PCR columns (lifetechnologies) and total RNA purified according to manufactureinstructions. Reduction of target mRNA expression is determined byqRT-PCR as previously described (4). Target mRNA levels were normalizedto cyclophilin levels and values were confirmed by RiboGreen.

5′-RACE

Male Balb/c mice are subcutaneously injected with 25 mg/kg ss-siRNAevery two hours for a combined dose of 100 mg/kg. Animals are sacrificed6 hr post final injection. Liver tissue is homogenized and purified asdescribed above. RNA Ligase Mediated Rapid Amplification of cDNA Ends(5′-RACE) (life technologies) is performed on 1 ug of purified total RNAfollowing manufacture instructions. PCR products are cloned using TopoTA-Machl-Tl cells (life technologies) as directed by manufactureprotocol. DNA is purified (QIAGEN) from cultured colonies and sequenced.

Determination of ssRNA Liver Concentrations by Hybridization-DependentNuclease ELISA

Liver samples (10-100 mg) are digested with 500 μl proteinase Kdigestion buffer (5U proteinase K (Sigma, St. Louis, Mo.)/1 ml Buffer G2(QIAGEN, Hilden, Germany)) for about 1 hr at 40° C. Standard curves areprepared with each analyte at 0.01 μM-5 μM in 500 μl control tissuehomogenate (100 mg control liver/ml proteinase K digestion buffer) anddigested 1 hr at 40° C. along with study samples. Study samples andstandard curves are diluted 1:100 in blank liver digest and 25 μlhybridized with 475 μl 3 nM complementary hybridization probe thatincluded a 5′ digoxigenin and 3′ biotin for 2 hr at room temperature.200 μl hybridization mix is added to NeutrAvidin-coated 96-well plates(Thermo, Rockford, Ill.) and incubated at room temperature for 1 hr.NeutrAvidin plates are washed with 0.2% Tween 20 in Tris-buffered saline(TBST) and 300 uL 50-300U/ml Si nuclease (Life Technologies, Carlsbad,Calif.) is added and incubated at room temperature for 2 hr. NeutrAvidinplates are washed with TBST and 200 μl 1:2000 anti-Digoxigenin-AP(Roche, Mannheim, Germany) is added and incubated for at least 1 hr atroom temperature. NeutrAvidin plates are washed with TBST and 200 μlAttophos (Promega, Madison Wis.) added and fluorescence monitored(excitation 450/50, emission 580/50) using a SpectraMax Geminimicroplate reader (Molecular Devices, Sunnyvale, Calif.). Catalysis ofAttophos is stopped by addition of 100 μl saturated solution of disodiumphosphate (25% Na2HPO4) before final quantitation of fluorescence onmicroplate reader.

Determination of Tissue Concentrations and Metabolites of ssRNAs UsingLC-MS

Tissues are minced and 50-200 mg samples homogenized in 500 μlhomogenization buffer (0.5% NP40 substitute (Calbiochem) inTris-buffered saline, pH8) with homogenization beads (Mo BioLaboratories, Carlsbad, Calif.) on a Retsch shaker (Mo Bio). Standardcurves of each ss-siRNA are established in 500 μl aliquots controltissue homogenate (50-200 mg/ml homogenization buffer). Controloligonucleotide is added as an internal standard (Int. Std.) to allstandard curves and study samples. Samples and curves are extracted withphenol/chloroform followed by solid-phase extraction (SPE) of theresulting aqueous extract using phenyl-functionalized silica sorbent(Biotage, Upsalla, Sweden). Eluate from SPE is dried down using a warmforced-air (argon) evaporator and reconstituted in 100-200 μl 4M urea,25 mM EDTA. Samples are analyzed by LC-MS. In brief, separation isaccomplished using an 1100 HPLCMS system (Agilent Technologies,Wilmington, Del.) consisting of a quaternary pump, UV detector, a columnoven, an autosampler, and a single quadrupole mass spectrometer. Samplesare injected on a X-bridge OST C18 column (2.1 mm×50 mm, 2.5 μmparticles; Waters, Milford, Mass.) equipped with a SecurityGuard C18guard column (Phenomenex, Torrance, Calif.). The columns are maintainedat 55° C. Tributylammonium acetate buffer (5 mM) and acetonitrile areused as the mobile phase at a flow rate of 0.3 ml/min. Acetonitrile isincreased (gradient) from 20% to 70% over 11 min. Mass measurements aremade online using a single quadrupole mass spectrometer scanning1000-2100 m/z in the negative ionization mode. Molecular masses aredetermined using ChemStation analysis package (Agilent, Santa Clara,Calif.). Manual evaluation is performed by comparing a table ofcalculated m/z values corresponding to potential metabolites with thepeaks present in a given spectrum. Peak areas from extracted ionchromatograms are determined for ss-siRNAs, 3′ N-1 metabolites, and Int.Std. and a trendline established using the calibration standards,plotting concentration of ssRNA against the ratio of the peak areasssRNA: Int. Std. Concentration of ssRNAs and 3′ N-1 metabolites in studysamples are determined using established trendlines and reported as μg/gtissue.

In Vitro mRNA Knockdown

Mouse Hepa1-6 cells are cultured in Dulbecco's modified Eagle Mediumsupplemented with 10% fetal bovine serum, 1% penicillin-steptomycin and1% sodium bicarbonate. These cells are plated in a 96-well cultureplates at a density of 3000 cells/well 24 h prior to transfection.Transfections are performed using Opti-MEM I Reduced Serum Media andLipofectamine RNAiMAX as previously described (30). Final siRNAconcentrations range from 100 to 1 nM for in vitro cell-based screenswith concentrations varying for ssRNA (100 nM, 10 nM) and dsRNA (100 nM,10 nM, and 1 nM) (see Tables). Final siRNA concentrations for thedose-response curves can range from 40 to 0.002 nM along an eight-point,4-fold titration curve. Twenty-four hours post-transfection cells arewashed with phosphate-buffered saline and processed using the TaqManGene Expression Cells-to-CT (Invitrogen), per manufacturer'sinstructions, to extract RNA, synthesize cDNA and perform RT-qPCR usingan target specific Taqman primer/probe set on an ABI Prism 7900HTSequence Detector. Reverse transcription conditions can be as follows:60 min at 37° C. followed by 5 min at 95° C. RT-qPCR conditions were asfollows: 2 min at 50° C., 10 min at 95° C., followed by 40 cycles of 15s at 95° C., and 1 min at 60° C. Gapdh mRNA levels can be used for datanormalization (Taqman part number 4308313). Knockdown of targets wascalculated as the percent knockdown in target cDNA measured inexperimentally treated cells relative to the target cDNA levels measuredin non-targeting, control-treated cells. The comparative Ct calculationmethod for knockdown has previously been described (31). Briefly,ΔCt=Ct_(Target)−Ct_(GADPH) and ΔΔCt=ΔCt(exp)−ΔCt(ctrl) and relativeexpression level=2^(−ΔΔCt) and % knockdown=100×(1−2^(−ΔΔct)). Potency(EC50) can be calculated using a four-parameter curve fit tool and Prismgraphing software (GraphPad Software).

Lipid Nanoparticle Formulation

siRNA lipid nanoparticles (LNPs) are assembled by simultaneous mixing ofa lipid mixture in ethanol with an aqueous solution of siRNA followed bydiafiltration. The cationic lipid CLinDMA(2-{4-[(3b)-cholest-5-en-3-yloxy]-butoxy}-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine),cholesterol and PEG-DMG(monomethoxy(polyethyleneglycol)-1,2-dimyristoylglycerol) are mixedtogether at a molar ratio of 50:44:6. PEG-DMG was purchased from NOFCorporation, cholesterol from Northern Lipids, and CLinDMA issynthesized by Merck & Co., Inc. Particle size is measured by dynamiclight scattering using a Wyatt DynaPro plate reader and percentencapsulation is determined using a SYBR Gold fluorescence assay(Invitrogen) and are within pre-established quality metrics.

qPCR Measurement

HCT-116 cells, cultured in McCoy's 5A Medium, supplemented with 10%fetal bovine serum and 1% penicillin-streptomycin, and plated at adensity of 6000 cells/well in 96-well culture plates 24 h prior totransfection, are transfected with Lipofectamine RNAiMax (Invitrogen)and Opti-MEM I Reduced Serum Media (GIBCO). Twenty-four hourspost-transfection, cells are rinsed with phosphate-buffered saline andprocessed with the Cells-to-CT Kit (Applied Biosystems). TaqMangene-specific probes are used on an ABI Prism 9700HT Sequence Detectorfor RT-qPCR. Reverse transcription conditions are as follows: 2 min at50° C., 10 min at 95° C., followed by 40 cycles of 15 sec at 95° C., and1 min at 60° C. GUSB mRNA levels can be used for data normalization.Knockdown is calculated as described above.

Microarray and Bioinformatics Analysis

HCT-116 cells are transfected with 10 nM miRNA using conventionaltechniques. RNA is extracted using RNeasy (Qiagen), amplified using theOvation protocol (Nugen), and profiled on custom Affymetrix arrays(Rosetta Custom Human 2.0, Affymetrix). Array signals are analyzed withAffymetrix GeneChip Operating Software and Affymetrix Power Tools. UTRhexamer and heptamer enrichment is analyzed using the hypergeometricdistribution.

Oligonucleotide sequences are shown in Tables 6-21.

Nucleoside and Linkage Modification Key for Examples of AgsrnaiCompounds Found in Tables 6-21

Each of the possible strand modifications in the following tables isdesignated according to the following abbreviations. Subscripts followthe standard canonical base indicated by a letter A, T, U, C or G wherea subscript indicates the base substitute, if any, and another subscriptthe sugar, sugar analog or sugar substitute being used. When the sugarused in a nucleoside is not specifically designated by a subscript it isribose. Letters indicate sugar modifications or sugar substitutes whilea number indicates base substitutions. The standard bases that can besubstituted for by a particular non-canonical base appear in parenthesisafter the name of the modified base in the key below. Otherabbreviations, as indicated below, are applied to 5′-end terminalmodifications, linkages or overhang precursors.

Nucleoside Sugars:

-   -   1) 2′-deoxyribose is D    -   2) 2′-fluoro is F    -   3) 2′-O-methyl is M    -   4) 2′-O-methyoxyethyl is moe    -   5) AENA is B    -   6) ALN is H    -   7) ANA is J    -   8) CENA is K    -   9) CRN is W for R monomer and V for Q monomer based    -   10) EA is E    -   11) FANA is Z    -   12) HM is Q    -   13) HNA is S    -   14) FHNA is Y    -   15) LNA is L    -   16) UNA is N    -   17) CeNA is O    -   18) F-CeNA is T    -   19) cEt is cet    -   20) Thio-LNA is TL    -   21) Amino-LNA is I

Nucleoside Bases:

-   -   1) Abasic (A, C, G or U) is 0    -   2) 2,6-Diaminopurine (A) is 2    -   3) 2-thiouracil (U) is 3    -   4) 4-thiouracil (C) is 4    -   5) 5-nitroindole (A, C, G or U) is 5    -   6) 2,4-difluorotoluene (A, C, G or U) is 6    -   7) 2-thiothymine (U) is 7    -   8) N⁴,N⁴-dimethylcytosine (A, C, G or U) is 8    -   9) Purine (A, C, G or U) is 9    -   10) 2-aminopurine (A, C, G or U) is 10    -   11) 5,6-dihydrouracil (A, C, G or U) is 11    -   12) Pseudouracil (U) is 12    -   13) 2,4-dichlorobenzene (A, C, G or U) is 13    -   14) 3-methyluracil (A, C, G or U) is 14    -   15) N²-cyclopentylguanine (G) is 15    -   16) N²-propyl-2-aminopurine (A) is 16    -   17) N²-cyclopentyl-2-aminopurine (A) is 17    -   18) 5-methyluracil (U) is 18    -   19) 5-methylcytosine (C) is 19

5′-End Terminal Modifications:

-   -   1) When the 5′-end 5′ carbon of the antisense strand is        manufactured with a phosphate group a P-precedes the terminal        nucleoside designation.    -   2) 5′-VP specifically designates the 5′-(E)-vinylphosphonate        bioisostere of phosphate that contains a double bond between the        5′ and 6′ carbons in a trans configuration as illustrated in        FIG. 15 where it is conjugated to a nucleoside. 5′-VP can be        conjugated to any terminal 5′-end agsRNAi nucleoside sugar or        sugar analog that is provided herein.

Linkages:

-   -   1) Phosphodiester is no linkage indicated    -   2) Phosphorothioate linkage is indicated by

3′-End Overhang Precursors:

-   -   Capital X represents some number of overhang precursor units        where the composition of the units and their number are chosen        from those provided herein. Overhang precursors can have any of        the units and linkages provided herein for this use.

Table 6 Examples of Murine/Human mIR-34a-5p ags-MIR Compositions

A. Murine/Human miR-34a-5p Sequence:

The miRBase accession numbers for murine and human miR-34a-5p areMI0000584 and MI0000268. The guide strand from each species has the samesequence. The sequence minus the overhang is as follows:

UGGCAGUGUCUUAGCUGGUUGUB. Some Examples of Ags-MiR Mimics of Murine/Human miR-34a:

As for any ssRNAi the endogenous miR-34a sequence minus the overhang canbe modified for basic nuclease resistance and then further modified byAGSD. The resulting compound can have any of the overhang precursorsprovided herein.

Since the targeting code for miR-34a is a seed sequence ags-MiR mimicsof miR-34a can be generated using the modular approach. A 9-mer 5′-endmodule sequence that includes the seed sequence of human and murinemiR-34a-5p suitable for use as a modular component is the following:

UGGCAGUGU

The 5′-end terminal nucleoside of a guide strand can have any basesuitable for use in the present invention. In this design example the5′-end terminal U found in the endogenous miRNA guide strand isretained.

This 9-mer 5′-end module can be used with any 10-mer seed vehiclesequence such as those shown in Table 19A. An example of such acombination is provided in the Modular Design Example Set #1.Alternatively, an 8-mer 5′-end module can be used with an 11-mer seedvehicle sequence such as those found in Table 3. An example of thiscombination is provided in Modular Design Example Set #2.

1) Modular Design Example Set #1:

In this example the seed vehicle sequence is vehicle 9y_2 found in Table19A. It is as follows:

CGCUUCUCUU

Any of the 5′-end nucleosides (P-U_(M) or P-A_(M)) shown in the examplesof agsRNAi compounds in Tables 6A and 6B can be replaced with any ofthose provided for herein including one of the 5′end nucleosidesselected from the group consisting of P-U_(F), P-U_(M), P-U_(N),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(Y), P-U_(O), P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z),P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V),P-G_(O), P-A_(F), P-A_(M), P-A_(L), P-A_(Z), P-A_(H), P-A_(B), P-A_(K),P-A_(Q), P-A_(S), P-A_(T), P-A_(W), P-A_(Y), P-A_(O), P-T_(L), P-T_(H),5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and5′-VP-T_(B).

Any of the nucleosides in Table 6A or 6B with an L modification(s) foundin one or more nucleosides in positions 2-19 can have any given L or setof Ls replaced with any of those sugar or sugar analogs provided forherein for positions 2-19 including one or more of the sugar, sugaranalogs or sugar substitutes independently selected from the groupconsisting of: S, J, W, V, Q, Y, O, T and cet (i.e., if multiple Ls arereplaced the selected replacements do not all have to be the same sugaror sugar analog).

Any of the nucleosides in Tables 6A or 6B with an L modification foundin the overhang precursor can have the L replaced with any of thoseunits and linkages provided for herein for overhang precursors includingone or more of the sugar, sugar analogs or sugar substitutesindependently selected from the group consisting of F, J, W, V, Y, T, TLand I.

Any of the compounds in Table 6A or 6B can have any of the overhangprecursors provided for herein.

TABLE 6A Compositions of Matter Suitable for Administration to a Subjectwith or without a Protective Carrier and for Any Other use as Providedfor Herein (5′-3′)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U_(F)~C_(M)U_(F3)~C_(M)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U_(F)~C_(M)U_(F3)~C_(M)~U₃~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M3)G_(F)~U_(M)C_(F)~G_(M)C_(F)~U_(M3)U_(F)~C_(M)U_(F)~C_(M)~U_(F)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U_(F3)~C_(M)U_(F3)~C_(M)~U_(F3)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U_(F)~C_(M)U_(F3)~C_(M4)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~U_(M3)C_(F)~G_(M)C_(F4)~U_(M3)U_(F)~C_(M4)U_(F3)~C_(M)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~U_(M)C_(F4)~G_(M)C_(F4)~U_(M3)U_(F)~C_(M4)U_(F)~C_(M4)~U_(F)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F4)~G_(M)C_(F4)~U_(M3)U_(F3)~C_(M4)U_(F3)~C_(M4)~U_(F3)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U_(F)~C_(M)U_(F12)~C_(M)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U_(F)~C_(M)U_(F12)~C_(M)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M12)G_(F)~U_(M)C_(F)~G_(M)C_(F)~U_(M12)U_(F)~C_(M)U_(F)~C_(M)~U_(F)~U_(M12)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U_(F12)~C_(M)U_(F12)~C_(M)~U_(F12)~U_(M12)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U_(F)~C_(M)U_(F12)~C_(M4)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~U_(M12)C_(F)~G_(M)C_(F4)~U_(M12)U_(F)~C_(M4)U_(F12)~C_(M)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M12)G_(F)~U_(M)C_(F4)~G_(M)C_(F4)~U_(M12)U_(F)~C_(M4)U_(F)~C_(M4)~U_(F)~U_(M12)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F4)~G_(M)C_(F4)~U_(M12)U_(F12)~C_(M4)U_(F12)~C_(M4)~U_(F12)~U_(M12)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M18)G_(F)~U_(M18)C_(F)~G_(M)C_(F)~U_(M18)U_(F)~C_(M)U_(F18)~C_(M)~U_(F18)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M)G_(F)~U_(M18)C_(F)~G_(M)C_(F)~U_(M18)U_(F)~C_(M)U_(F18)~C_(M)~U_(F18)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M18)G_(F)~U_(M)C_(F)~G_(M)C_(F)~U_(M18)U_(F)~C_(M)U_(F)~C_(M)~U_(F)~U_(M18)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M18)G_(F)~U_(M18)C_(F)~G_(M)C_(F)~U_(M18)U_(F18)~C_(M)U_(F18)~C_(M)~U_(F18)~U_(M18)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M18)G_(F)~U_(M18)C_(F)~G_(M)C_(F)~U_(M18)U_(F)~C_(M)U_(F18)~C_(M4)~U_(F18)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~U_(M18)C_(F)~G_(M)C_(F4)~U_(M18)U_(F)~C_(M4)U_(F18)~C_(M)~U_(F18)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M18)G_(F)~U_(M)C_(F4)~G_(M)C_(F4)~U_(M18)U_(F)~C_(M4)U_(F)~C_(M4)~U_(F)~U_(M18)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M18)G_(F)~U_(M18)C_(F4)~G_(M)C_(F4)~U_(M18)U_(F18)~C_(M4)U_(F18)~C_(M4)~U_(F18)~U_(M18)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U~C_(M)U_(F3)~C_(M)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U~C_(M)U_(F3)~C_(M)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M3)G_(F)~U_(M)C_(F)~G_(M)C_(F)~U_(M3)U~C_(M)U_(F)~C_(M)~U_(F)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U~C_(M)U_(F3)~C_(M)~U_(F3)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F)~G_(M)C_(F)~U_(M3)U~C_(M)U_(F3)~C_(M4)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~U_(M3)C_(F)~G_(M)C_(F4)~U_(M3)U~C_(M4)U_(F3)~C_(M)~U_(F3)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~U_(M)C_(F4)~G_(M)C_(F4)~U_(M3)U~C_(M4)U_(F)~C_(M4)~U_(F)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~U_(M3)C_(F4)~G_(M)C_(F4)~U_(M3)U~C_(M4)U_(F3)~C_(M4)~U_(F3)~U_(M3)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U~C_(M)U_(F12)~C_(M)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M)~G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U~C_(M)U_(F12)~C_(M)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M12)G_(F)~U_(M)C_(F)~G_(M)C_(F)~U_(M12)U~C_(M)U_(F)~C_(M)~U_(F)~U_(M12)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U~C_(M)U_(F12)~C_(M)~U_(F12)~U_(M12)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M12)G_(F)~U_(M12)C_(F)~G_(M)C_(F)~U_(M12)U~C_(M)U_(F12)~C_(M4)~U_(F12)~U_(M)~A_(F)~G_(F)~A_(M)P-U_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~U_(M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~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U_(F)~C_(L)U_(F3)~C_(M)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U_(F)~C_(L)U_(F3)~C_(M)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M3)G_(L)~U_(M)C_(F)~G_(M)C_(L)~U_(M3)U_(F)~C_(L)U_(F)~C_(M)~U_(L)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U_(F3)~C_(L)U_(F3)~C_(M)~U_(L3)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U_(F)~C_(L)U_(F3)~C_(M4)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~U_(M3)C_(F)~G_(M)C_(L4)~U_(M3)U_(F)~C_(L4)U_(F3)~C_(M)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~U_(M)C_(F4)~G_(M)C_(L4)~U_(M3)U_(F)~C_(L4)U_(F)~C_(M4)~U_(L)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F4)~G_(M)C_(L4)~U_(M3)U_(F3)~C_(L4)U_(F3)~C_(M4)~U_(L3)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U_(F)~C_(L)U_(F12)~C_(M)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U_(F)~C_(L)U_(F12)~C_(M)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M12)G_(L)~U_(M)C_(F)~G_(M)C_(L)~U_(M12)U_(F)~C_(L)U_(F)~C_(M)~U_(L)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U_(F12)~C_(L)U_(F12)~C_(M)~U_(L12)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U_(F)~C_(L)U_(F12)~C_(M4)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~U_(M12)C_(F)~G_(M)C_(L4)~U_(M12)U_(F)~C_(L4)U_(F12)~C_(M)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~U_(M)C_(F4)~G_(M)C_(L4)~U_(M12)U_(F)~C_(L4)U_(F)~C_(M4)~U_(L)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F4)~G_(M)C_(L4)~U_(M12)U_(F12)~C_(L4)U_(F12)~C_(M4)~U_(L12)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U_(F)~C_(L)U_(F18)~C_(M)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U_(F)~C_(L)U_(F18)~C_(M)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M18)G_(L)~U_(M)C_(F)~G_(M)C_(L)~U_(M18)U_(F)~C_(L)U_(F)~C_(M)~U_(L)~U_(M18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U_(F18)~C_(L)U_(F18)~C_(M)~U_(L18)~U_(M18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U_(F)~C_(L)U_(F18)~C_(M4)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~U_(M18)C_(F)~G_(M)C_(L4)~U_(M18)U_(F)~C_(L4)U_(F18)~C_(M)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~U_(M)C_(F4)~G_(M)C_(L4)~U_(M18)U_(F)~C_(L4)U_(F)~C_(M4)~U_(L)~U_(M18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F4)~G_(M)C_(L4)~U_(M18)U_(F18)~C_(L4)U_(F18)~C_(M4)~U_(L18)~U_(M18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U~C_(L)U_(F3)~C_(M)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U~C_(L)U_(F3)~C_(M)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M3)G_(L)~U_(M)C_(F)~G_(M)C_(L)~U_(M3)U~C_(L)U_(F)~C_(M)~U_(L)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U~C_(L)U_(F3)~C_(M)~U_(L3)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F)~G_(M)C_(L)~U_(M3)U~C_(L)U_(F3)~C_(M4)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~U_(M3)C_(F)~G_(M)C_(L4)~U_(M3)U~C_(L4)U_(F3)~C_(M)~U_(L3)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~U_(M)C_(F4)~G_(M)C_(L4)~U_(M3)U~C_(L4)U_(F)~C_(M4)~U_(L)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~U_(M3)C_(F4)~G_(M)C_(L4)~U_(M3)U~C_(L4)U_(F3)~C_(M4)~U_(L3)~U_(M3)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U~C_(L)U_(F12)~C_(M)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U~C_(L)U_(F12)~C_(M)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M12)G_(L)~U_(M)C_(F)~G_(M)C_(L)~U_(M12)U~C_(L)U_(F)~C_(M)~U_(L)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U~C_(L)U_(F12)~C_(M)~U_(L12)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F)~G_(M)C_(L)~U_(M12)U~C_(L)U_(F12)~C_(M4)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~U_(M12)C_(F)~G_(M)C_(L4)~U_(M12)U~C_(L4)U_(F12)~C_(M)~U_(L12)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~U_(M)C_(F4)~G_(M)C_(L4)~U_(M12)U~C_(L4)U_(F)~C_(M4)~U_(L)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~U_(M12)C_(F4)~G_(M)C_(L4)~U_(M12)U~C_(L4)U_(F12)~C_(M4)~U_(L12)~U_(M12)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U~C_(L)U_(F18)~C_(M)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U~C_(L)U_(F18)~C_(M)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M18)G_(L)~U_(M)C_(F)~G_(M)C_(L)~U_(M18)U~C_(L)U_(F)~C_(M)~U_(F)~U_(L18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U~C_(L)U_(F18)~C_(M)~U_(L18)~U_(M18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F)~G_(M)C_(L)~U_(M18)U~C_(L)U_(F18)~C_(M4)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~U_(M18)C_(F)~G_(M)C_(L4)~U_(M18)U~C_(L4)U_(F18)~C_(M)~U_(L18)~U_(M)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~U_(M)C_(F4)~G_(M)C_(L4)~U_(M18)U~C_(L4)U_(F)~C_(M4)~U_(L)~U_(M18)~A_(L)~G_(L)~A_(M)P-U_(M)~G_(L)~G_(M)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~U_(M18)C_(F4)~G_(M)C_(L4)~U_(M18)U~C_(L4)U_(F18)~C_(M4)~U_(L18)~U_(M18)~A_(L)~G_(L)~A_(M)

2) Modular Design Example Set #2

The 11-mer seed vehicle referred to as sequence no. 1 in Table 3 is usedin the ags-MiR compounds illustrated in Table 6B. It has the followingsequence:

GUUCUUUCUUU

It has to be used with an 8-mer 5′-end module that includes the seedsequence of human and murine miR-34a-5p. In addition to being onenucleoside shorter on the 3′-end this sequence has an A rather than theU in the 5′-end terminal nucleoside of the 5′end module used in ModularDesign Example Set #1 in some of the following examples. Thisillustrates the fact this position can have any of the bases providedherein.

AGGCAGUG

TABLE 6B Compositions of Matter Suitable for Administration to a Subjectwith or without a Protective Carrier and for Any Other use as Providedfor Herein (5′-3′)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F3)~U_(M3)C_(F4)~U_(M3)U_(F)~U_(M3)C_(F)~U_(M3)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F3)~U_(M3)C_(F4)~U_(M3)U_(F)~U_(M3)C_(F4)~U_(M)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~G_(M)U_(F3)~U_(M3)C_(F4)~U_(M3)U_(F3)~U_(M3)C_(F4)~U_(M)~U_(F3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F12)~U_(M12)C_(F4)~U_(M12)U_(F)~U_(M12)C_(F)~U_(M12)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F12)~U_(M12)C_(F4)~U_(M12)U_(F)~U_(M12)C_(F4)~U_(M)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M12)G_(F)~G_(M)U_(F12)~U_(M12)C_(F4)~U_(M12)U_(F12)~U_(M12)C_(F4)~U_(M)~U_(F12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F18)~U_(M18)C_(F4)~U_(M18)U_(F)~U_(M18)C_(F)~U_(M18)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F18)~U_(M18)C_(F4)~U_(M18)U_(F)~U_(M18)C_(F4)~U_(M)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M18)G_(F)~G_(M)U_(F18)~U_(M18)C_(F4)~U_(M18)U_(F18)~U_(M18)C_(F4)~U_(M)~U_(F18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F3)~U_(M3)C_(F4)~U_(M3)U~U_(M3)C_(F)~U_(M3)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F3)~U_(M3)C_(F4)~U_(M3)U~U_(M3)C_(F4)~U_(M)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M3)G_(F)~G_(M)U_(F3)~U_(M3)C_(F4)~U_(M3)U~U_(M3)C_(F4)~U_(M)~U_(F3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F12)~U_(M12)C_(F4)~U_(M12)U~U_(M12)C_(F)~U_(M12)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F12)~U_(M12)C_(F4)~U_(M12)U~U_(M12)C_(F4)~U_(M)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M12)G_(F)~G_(M)U_(F12)~U_(M12)C_(F4)~U_(M12)U~U_(M12)C_(F4)~U_(M)~U_(F12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F18)~U_(M18)C_(F4)~U_(M18)U~U_(M18)C_(F)~U_(M18)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M)G_(F)~G_(M)U_(F18)~U_(M18)C_(F4)~U_(M18)U~U_(M18)C_(F4)~U_(M)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(M)C_(F4)~A_(M)G_(F)~U_(M18)G_(F)~G_(M)U_(F18)~U_(M18)C_(F4)~U_(M18)U~U_(M18)C_(F4)~U_(M)~U_(F18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F)~U_(M)C_(L)~U_(M)U_(F)~U_(L)C_(F)~U_(M)~U_(L)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F)~U_(M)C_(L)~U_(M)U~U_(L)C_(F)~U_(M)~U_(L)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(L4)~U_(M3)U_(F)~U_(L3)C_(F)~U_(M3)~U_(L3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(L4)~U_(M3)U_(F)~U_(L3)C_(F4)~U_(M)~U_(L3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M3)G_(F)~G_(L)U_(F3)~U_(M3)C_(L4)~U_(M3)U_(F3)~U_(L3)C_(F4)~U_(M)~U_(L3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(L4)~U_(M12)U_(F)~U_(L12)C_(F)~U_(M12)~U_(L12)~U_(M)~G_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(L4)~U_(M12)U_(F)~U_(L12)C_(F4)~U_(M)~U_(L12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M12)G_(F)~G_(L)U_(F12)~U_(M12)C_(L4)~U_(M12)U_(F12)~U_(L12)C_(F4)~U_(M)~U_(L12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(r)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(L4)~U_(M18)U_(F)~U_(L18)C_(F)~U_(M18)~U_(L18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(L4)~U_(M18)U_(F)~U_(L18)C_(F4)~U_(M)~U_(L18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M18)G_(F)~G_(L)U_(F18)~U_(M18)C_(L4)~U_(M18)U_(F18)~U_(L18)C_(F4)~U_(M)~U_(L18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(L4)~U_(M3)U~U_(L3)C_(F)~U_(M3)~U_(L3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(L4)~U_(M3)U~U_(L3)C_(F4)~U_(M)~U_(L3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M3)G_(F)~G_(L)U_(F3)~U_(M3)C_(L4)~U_(M3)U~U_(L3)C_(F4)~U_(M)~U_(L3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(L4)~U_(M12)U~U_(L12)C_(F)~U_(M12)~U_(L12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(L4)~U_(M12)U~U_(L12)C_(F4)~U_(M)~U_(L12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M12)G_(F)~G_(L)U_(F12)~U_(M12)C_(L4)~U_(M12)U~U_(L12)C_(F4)~U_(M)~U_(L12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(L4)~U_(M18)U~U_(L18)C_(F)~U_(M18)~U_(L18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(L4)~U_(M18)U~U_(L18)C_(F4)~U_(M)~U_(L18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(M)G_(L)~U_(M18)G_(F)~G_(L)U_(F18)~U_(M18)C_(L4)~U_(M18)U~U_(L18)C_(F4)~U_(M)~U_(L18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F)~U_(L)C_(F)~U_(M)U_(F)~U_(M)C_(F)~U_(L)~U_(F)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F)~U_(L)C_(F)~U_(M)U~U_(M)C_(F)~U_(L)~U_(F)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F3)~U_(L3)C_(F4)~U_(M3)U_(F)~U_(M3)C_(F)~U_(L3)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F3)~U_(L3)C_(F4)~U_(M3)U_(F)~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~G_(M)U_(F3)~U_(L3)C_(F4)~U_(M3)U_(F3)~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F12)~U_(L12)C_(F4)~U_(M12)U_(F)~U_(M12)C_(F)~U_(L12)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F12)~U_(L12)C_(F4)~U_(M12)U_(F)~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~G_(M)U_(F12)~U_(L12)C_(F4)~U_(M12)U_(F12)~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F18)~U_(L18)C_(F4)~U_(M18)U_(F)~U_(M18)C_(F)~U_(L18)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F18)~U_(L18)C_(F4)~U_(M18)U_(F)~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~G_(M)U_(F18)~U_(L18)C_(F4)~U_(M18)U_(F18)~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F3)~U_(L3)C_(F4)~U_(M3)U~U_(M3)C_(F)~U_(L3)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F3)~U_(L3)C_(F4)~U_(M3)U~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M3)G_(L)~G_(M)U_(F3)~U_(L3)C_(F4)~U_(M3)U~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F12)~U_(L12)C_(F4)~U_(M12)U~U_(M12)C_(F)~U_(L12)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F12)~U_(L12)C_(F4)~U_(M12)U~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M12)G_(L)~G_(M)U_(F12)~U_(L12)C_(F4)~U_(M12)U~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F18)~U_(L18)C_(F4)~U_(M18)U~U_(M18)C_(F)~U_(L18)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M)G_(L)~G_(M)U_(F18)~U_(L18)C_(F4)~U_(M18)U~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(F)~G_(L)C_(F4)~A_(L)G_(F)~U_(M18)G_(L)~G_(M)U_(F18)~U_(L18)C_(F4)~U_(M18)U~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F)~U_(M)C_(F)~U_(L)U_(F)~U_(M)C_(F)~U_(L)~U_(F)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F)~U_(M)C_(F)~U_(L)U~U_(M)C_(F)~U_(L)~U_(F)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(F4)~U_(L3)U_(F)~U_(M3)C_(F)~U_(L3)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(F4)~U_(L3)U_(F)~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M3)G_(F)~G_(L)U_(F3)~U_(M3)C_(F4)~U_(L3)U_(F3)~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(F4)~U_(L12)U_(F)~U_(M12)C_(F)~U_(L12)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(F4)~U_(L12)U_(F)~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M12)G_(F)~G_(L)U_(F12)~U_(M12)C_(F4)~U_(L12)U_(F12)~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(F4)~U_(L18)U_(F)~U_(M18)C_(F)~U_(L18)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(F4)~U_(L18)U_(F)~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M18)G_(F)~G_(L)U_(F18)~U_(M18)C_(F4)~U_(L18)U_(F18)~U_(M18)C_(F4)~U_(M)~U_(F18)~U_(M18)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(F4)~U_(L3)U~U_(M3)C_(F)~U_(L3)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F3)~U_(M3)C_(F4)~U_(L3)U~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(M)C_(F4)~A_(M)G_(L)~U_(M3)G_(F)~G_(L)U_(F3)~U_(M3)C_(F4)~U_(L3)U~U_(M3)C_(F4)~U_(L)~U_(F3)~U_(M3)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(F4)~U_(L12)U~U_(M12)C_(F)~U_(L12)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F12)~U_(M12)C_(F4)~U_(L12)U~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M12)G_(F)~G_(L)U_(F12)~U_(M12)C_(F4)~U_(L12)U~U_(M12)C_(F4)~U_(L)~U_(F12)~U_(M12)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(F4)~U_(L18)U~U_(M18)C_(F)~U_(L18)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M)G_(F)~G_(L)U_(F18)~U_(M18)C_(F4)~U_(L18)U~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M)~G_(L)~C_(L)~U_(F)P-A_(M)~G_(L)~G_(M)C_(F4)~A_(M)G_(L)~U_(M18)G_(F)~G_(L)U_(F18)~U_(M18)C_(F4)~U_(L18)U~U_(M18)C_(F4)~U_(L)~U_(F18)~U_(M18)~G_(L)~C_(L)~U_(F)

Table 7 Examples of Murine/Human MiR-34a-5P ags-IMIR Compositions

A. Murine/Human miR-34a-5p Sequence and Antisense Sequence:

The miRBase accession numbers for murine and human miR-34a-5p areMI0000584 and MI0000268. The guide strand from each species has the samesequence. The sequence minus the overhang is as follows:

UGGCAGUGUCUUAGCUGGUUGU

Hence the antisense sequence is as follows:

ACAACCAGCUAAGACACUGCCA

Any of the 5′-end nucleosides (P-A_(F)) shown in the examples of agsRNAicompounds in Table 7A or 7B can be replaced with any of those providedfor herein including one of the 5′end nucleosides selected from thegroup consisting of P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z),P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V),P-G_(O), P-A_(M), P-A_(L), P-A_(Z), P-A_(H), P-A_(B), P-A_(K), P-A_(Q),P-A_(S), P-A_(T), P-A_(W), P-A_(V), P-A_(O), P-T_(L), P-T_(H),5′-VP-A_(Z), 5′-VP-A_(K), 5′-VP-A_(Q), 5′-VP-A_(B), 5′-VP-T_(moe),5′-VP-T_(E), 5′-VP-U_(E), 5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and5′-VP-T_(B).

Any of the nucleosides in Table 7A or 7B with an L modification(s) foundin one or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the nucleosides in Tables 7A or 7B with an L modification foundin the overhang precursor can have the L replaced with any of thoseunits and linkages provided for herein for overhang precursors includingone or more of the sugar, sugar analogs or sugar substitutesindependently selected from the group consisting of: F, J, W, V, Y, T,TL and I.

Any of the compounds in Table 7A and 7B can any of those units andlinkages provided for herein for overhang precursors.

B. Examples of agsRNAi Compounds:

TABLE 7A Compositions of Matter Suitable for Administration to a Subjectwith or without a Protective Carrier and for Any Other use as Providedfor Herein (5′-3′)P-A_(F)~C_(M)~A_(F)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M)U_(F)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M)C_(F4)~C_(M4)A_(F)~G_(F)C_(M)~U_(F)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M)U_(F)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M)C_(F4)~C_(M4)A_(F)~G_(F)C_(M)~U_(F)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M4)U_(F)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M)C_(F4)~C_(M4)A_(F)~G_(F)C_(M4)~U_(F)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M)U_(F3)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M)C_(F4)~C_(M4)A_(F)~G_(F)C_(M)~U_(F3)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M4)U_(F3)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M)C_(F4)~C_(M4)A_(F)~G_(F)C_(M4)~U_(F3)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F2)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M)U_(F)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M2)C_(F4)~C_(M4)A_(F)~G_(F)C_(M)~U_(F)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F2)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M)U_(F)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M2)C_(F4)~C_(M4)A_(F)~G_(F)C_(M)~U_(F)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F2)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M4)U_(F)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M2)C_(F4)~C_(M4)A_(F)~G_(F)C_(M4)~U_(F)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F2)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M)U_(F3)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M2)C_(F4)~C_(M4)A_(F)~G_(F)C_(M)~U_(F3)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F2)A_(M)~C_(F4)C_(M4)~A_(F)G_(F)~C_(M4)U_(F3)~A_(M)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(F)~A_(M2)C_(F4)~C_(M4)A_(F)~G_(F)C_(M4)~U_(F3)A_(M)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(M4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)~C_(F)C_(M)~A_(L)G_(F)~C_(M)U_(F)~A_(F)A_(L)~G_(M)A~C_(M)~A_(F)~C_(L)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(M4)A_(L)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(M4)A_(L)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M4)U_(F)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(M4)A_(L)~G_(F)C_(M4)~U_(F)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M)U_(F3)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(M4)A_(L)~G_(F)C_(M)~U_(F3)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M4)U_(F3)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(M4)A_(L)~G_(F)C_(M4)~U_(F3)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(M4)A_(L)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(M4)A_(L)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M4)U_(F)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(M4)A_(L)~G_(F)C_(M4)~U_(F)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M)U_(F3)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(M4)A_(L)~G_(F)C_(M)~U_(F3)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(M4)~A_(L)G_(F)~C_(M4)U_(F3)~A_(L)A_(F)~G_(M)A~C_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(M4)A_(L)~G_(F)C_(M4)~U_(F3)A_(L)~A_(F)G_(M)~AC_(M4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F)C_(M)~A_(L)G_(F)~C_(M)U_(F)~A_(F)A_(L)~G_(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_(L4)A_(F)~G_(F)C_(M4)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F3)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F3)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M4)U_(F3)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M4)~U_(F3)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(F)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F)C_(L)~A_(F)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(L)A~C_(L)~A_(F)~C_(L)~U_(F)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M4)U_(F)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(L4)A_(F)~G_(F)C_(M4)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F3)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F3)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M4)U_(F3)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M)C_(F4)~C_(L4)A_(F)~G_(F)C_(M4)~U_(F3)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M4)U_(F)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M4)~U_(F)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M)U_(F3)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M)~U_(F3)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L2)A_(M)~C_(F4)C_(L4)~A_(F)G_(F)~C_(M4)U_(F3)~A_(L)A_(F)~G_(L)A~C_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)P-A_(F)~C_(M)~A_(L)~A_(M2)C_(F4)~C_(L4)A_(F)~G_(F)C_(M4)~U_(F3)A_(L)~A_(F)G_(L)~AC_(L4)~A_(F)~C_(L4)~U_(F3)~G_(M)~A_(L)~G_(L)~G_(M)

TABLE 7B Compositions of Matter Suitable For Use in vitro or in aSubject with a Protective Carrier (5′-3′)P-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F2)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F2)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F2)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F2)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F2)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F2)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F2)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F2)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F2)A_(F)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F2)~C_(F4)~C_(F4)~A_(F)G_(F)C_(F4)U_(F3)~A_(F)A_(F)G_(F)A~C_(F4)~A_(F)~C_(F4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F)~C_(F)~A_(L)G_(F)C_(F)U_(F)~A_(F)A_(L)G_(F)A~C_(F)~A_(F)~C_(L)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(F2)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(F4)~A_(L)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(F)A~C_(F4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(F)A_(L)~C_(F)~C_(F)~A_(F)G_(L)C_(F)U_(F)~A_(F)A_(L)G_(F)A~C_(F)~A_(F)~C_(L)U_(F)~G_(F)A_(L)~G_(L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)~C_(L)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L)~A_(F)~C_(L)U_(F-)G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L2)A_(F)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~GP-A_(F)~C_(F)~A_(L)A_(F2)~C_(F4)~C_(L4)~A_(F)G_(F)C_(F4)U_(F3)~A_(L)A_(F)G_(L)A~C_(L4)~A_(F)~C_(L4)U_(F3)~G_(F)A_(L)~G_(L)~G

Table 8 Examples of Murine/Human PTEN ags-siRNA Compositions A.Murine/Human PTEN Antisense Sequence:

UUGUCUCUGGUCCUUACU

Lima et al. (Cell 150: 883-94, 2012) used this sequence to generatessRNAi compounds against human/murine PTEN including the following:

5′-VP-T_(moe)~U_(F)~G_(M)U_(F)~C_(M)U_(F)~C_(M)U_(F)~G_(M)G_(F)~U_(M)C_(F)~C_(M)U_(F)~U_(M)~A_(F)~C_(M)~U_(F)~U_(M)~A_(moe)~A_(moe)P-T_(moe)~U_(F)~G_(M)U_(F)~C_(M)U_(F)~C_(M)U_(F)~G_(M)G_(F)~U_(M)C_(F)~C_(M)U_(F)~U_(M)~A_(F)~C_(M)~U_(F)~U_(M)~A_(moe)~A_(moe)P-U_(M)~U_(F)G_(M)U_(F)C_(M)U_(F)C_(M)U_(F)G_(M)G_(F)U_(M)C_(F)~C_(M)~U_(F)~U_(M)~A_(F)~C_(M)~U_(F)~U_(M)~A_(moe)~A_(moe)

Any of the 5′-end nucleosides (P-U_(F) or P-U_(M)) shown in the examplesof agsRNAi compounds in Tables 8A and 8B can be replaced with any ofthose provided for herein including one of the 5′end nucleosidesselected from the group consisting of: P-G_(F), P-G_(M), P-G_(N),P-G_(L), P-G_(Z), P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T),P-G_(W), P-G_(V), P-G_(O), P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z),P-C_(H), P-C_(B), P-C_(K), P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V),P-U_(F), P-U_(M), P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q),P-U_(S), P-U_(T), P-U_(W), P-U_(V), P-U_(O), P-T_(F), P-T_(H),5′-VP-U_(Z), 5′-VP-U_(K), 5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe),5′-VP-T_(E), 5′-VP-U_(E), 5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and5′-VP-T_(B).

Any of the nucleosides in Table 8A or 8B with an L modification(s) foundin one or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the nucleosides in Tables 8A or 8B with an L modification foundin the overhang precursor can have the L replaced with any of thoseunits and linkages provided for herein for overhang precursors includingone or more of the sugar, sugar analogs or sugar substitutesindependently selected from the group consisting of: F, J, W, V, Y, T,TL and I.

Any of the compounds in Tables 8A and 8B can any of those units andlinkages provided for herein for overhang precursors.

B. Examples of agsRNAi Compounds:

TABLE 8A Composition of Matter Preferred use In Vitro or with aProtective Carrier In Vivo (5′-3′)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F)~C_(F4)U_(F12)~G_(F)G_(F)U_(F)~C_(F)~C_(F4)UU_(F12)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F)~C_(F4)U_(F3)~G_(F)G_(F)U_(F)~C_(F)~C_(F4)UU_(F3)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F)~C_(F4)U_(F18)~G_(F)G_(F)U_(F)~C_(F)~C_(F4)UU_(F18)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F4)U_(F)~C_(F)U_(F12)~G_(F)G_(F)U_(F)~C_(F4)~C_(F)UU_(F12)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F4)U_(F)~C_(F)U_(F3)~G_(F)G_(F)U_(F)~C_(F4)~C_(F)UU_(F3)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F4)U_(F)~C_(F)U_(F18)~G_(F)G_(F)U_(F)~C_(F4)~C_(F)UU_(F18)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F4)U_(F)~C_(F4)U_(F12)~G_(F)G_(F)U_(F)~C_(F4)~C_(F4)UU_(F12)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F4)U_(F)~C_(F4)U_(F3)~G_(F)G_(F)U_(F)~C_(F4)~C_(F4)UU_(F3)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F4)U_(F)~C_(F4)U_(F18)~G_(F)G_(F)U_(F)~C_(F4)~C_(F4)UU_(F18)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F)~C_(F)U_(F12)~G_(F)G_(F)U_(F12)~C_(F)~C_(F)UU_(F12)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F)~C_(F)U_(F3)~G_(F)G_(F)U_(F3)~C_(F)~C_(F)UU_(F3)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F)~C_(F)U_(F18)~G_(F)G_(F)U_(F18)~C_(F)~C_(F)UU_(F18)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F12)~C_(F)U_(F12)~G_(F)G_(F)U_(F12)~C_(F)~C_(F)UU_(F12)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F3)~C_(F)U_(F3)~G_(F)G_(F)U_(F3)~C_(F)~C_(F)UU_(F3)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F18)~C_(F)U_(F18)~G_(F)G_(F)U_(F18)~C_(F)~C_(F)UU_(F18)~A_(F)~C_(F)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F12)~C_(F)U_(F12)~G_(F)G_(F)U_(F12)~C_(F)~C_(F)UU_(F12)~A_(F)~C_(F)U_(F12)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F3)~C_(F)U_(F3)~G_(F)G_(F)U_(F3)~C_(F)~C_(F)UU_(F3)~A_(F)~C_(F)U_(F3)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F18)~C_(F)U_(F18)~G_(F)G_(F)U_(F18)~C_(F)~C_(F)UU_(F18)~A_(F)~C_(F)U_(F18)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F)~C_(F4)U_(F12)~G_(F)G_(F)U_(F12)~C_(F4)~C_(F)UU_(F12)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F)~C_(F4)U_(F3)~G_(F)G_(F)U_(F3)~C_(F4)~C_(F)UU_(F3)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F)~C_(F4)U_(F18)~G_(F)G_(F)U_(F18)~C_(F4)~C_(F)UU_(F18)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F12)~C_(F4)U_(F12)~G_(F)G_(F)U_(F12)~C_(F4)~C_(F)UU_(F12)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F3)~C_(F4)U_(F3)~G_(F)G_(F)U_(F3)~C_(F4)~C_(F)UU_(F3)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F18)~C_(F4)U_(F18)~G_(F)G_(F)U_(F18)~C_(F4)~C_(F)UU_(F18)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F)U_(F12)~C_(F4)U_(F12)~G_(F)G_(F)U_(F12)~C_(F4)~C_(F)UU_(F12)~A_(F)~C_(F4)U_(F12)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F)U_(F3)~C_(F4)U_(F3)~G_(F)G_(F)U_(F3)~C_(F4)~C_(F)UU_(F3)~A_(F)~C_(F4)U_(F3)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F)U_(F18)~C_(F4)U_(F18)~G_(F)G_(F)U_(F18)~C_(F4)~C_(F)UU_(F18)~A_(F)~C_(F4)U_(F18)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F4)U_(F)~C_(F4)U_(F12)~G_(F)G_(F)U_(F12)~C_(F4)~C_(F4)UU_(F12)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F4)U_(F)~C_(F4)U_(F3)~G_(F)G_(F)U_(F3)~C_(F4)~C_(F4)UU_(F3)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F4)U_(F)~C_(F4)U_(F18)~G_(F)G_(F)U_(F18)~C_(F4)~C_(F4)UU_(F18)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F4)U_(F12)~C_(F4)U_(F12)~G_(F)G_(F)U_(F12)~C_(F4)~C_(F4)UU_(F12)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F4)U_(F3)~C_(F4)U_(F3)~G_(F)G_(F)U_(F3)~C_(F4)~C_(F4)UU_(F3)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F4)U_(F18)~C_(F4)U_(F18)~G_(F)G_(F)U_(F18)~C_(F4)~C_(F4)UUFIG~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F12)~C_(F4)U_(F12)~C_(F4)U_(F12)~G_(F)G_(F)U_(F12)~C_(F4)~C_(F4)UU_(F12)~A_(F)~C_(F4)U_(F12)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F3)~C_(F4)U_(F3)~C_(F4)U_(F3)~G_(F)G_(F)U_(F3)~C_(F4)~C_(F4)UU_(F3)~A_(F)~C_(F4)U_(F3)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F18)~C_(F4)U_(F18)~C_(F4)U_(F18)~G_(F)G_(F)U_(F18)~C_(F4)~C_(F4)UU_(F18)~A_(F)~C_(F4)U_(F18)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F)~C_(F4)U_(F)~C_(F4)A_(F)~G_(F)G_(F)U_(F)~C_(F4)~C_(F4)UU_(F)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(F)U_(F)~C_(F4)U_(F)~C_(F4)U_(F)~A_(F)G_(F)U_(F)~C_(F4)~C_(F4)UU_(F)~A_(F)~C_(F4)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F)~C_(F)U_(L)C_(F)U_(F)~G_(F)G_(F)U_(F)~C_(L)~C_(F)UU_(F)~A_(L)~C_(F)U_(L)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F)U_(L)C_(F4)U_(F12)~G_(F)G_(F)U_(F)~C_(L)~C_(F4)UU_(F12)~A_(L)~C_(F)U_(L)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)C_(F4)U_(F3)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)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)~C_(F)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F)U_(L)~C_(F)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F)U_(L)~C_(F)U_(F12)~G_(F)G_(L)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)~C_(F)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F)U_(L)~C_(F)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F)U_(L)~C_(F)U_(F12)~G_(F)G_(L)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F12)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)~C_(F)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F3)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F)U_(L)~C_(F)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F18)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F)U_(L)~C_(F4)U_(F12)~G_(F)G_(L)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)~C_(F4)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F)U_(L)~C_(F4)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F)U_(L)~C_(F4)U_(F12)~G_(F)G_(L)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)~C_(F4)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F)U_(L)~C_(F4)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F)U_(L)~C_(F4)U_(F12)~G_(F)G_(L)U_(F12)~C_(F4)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F12)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F)U_(L)~C_(F4)U_(F3)~G_(F)G_(L)U_(F3)~C_(F4)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F3)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F)U_(L)~C_(F4)U_(F18)~G_(F)G_(L)U_(F18)~C_(F4)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F18)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F4)U_(L)~C_(F4)U_(F12)~G_(F)G_(L)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F4)U_(L)~C_(F4)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F4)U_(L)~C_(F4)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F4)U_(L)~C_(F4)U_(F12)~G_(F)G_(L)U_(F12)~C_(F)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F4)U_(L)~C_(F4)U_(F3)~G_(F)G_(L)U_(F3)~C_(F)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F4)U_(L)~C_(F4)U_(F18)~G_(F)G_(L)U_(F18)~C_(F)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F12)~C_(F4)U_(L)~C_(F4)U_(F12)~G_(F)G_(L)U_(F12)~C_(F4)~C_(L)UU_(F12)~A_(F)~C_(L)U_(F12)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F3)~C_(F4)U_(L)~C_(F4)U_(F3)~G_(F)G_(L)U_(F3)~C_(F4)~C_(L)UU_(F3)~A_(F)~C_(L)U_(F3)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F18)~C_(F4)U_(L)~C_(F4)U_(F18)~G_(F)G_(L)U_(F18)~C_(F4)~C_(L)UU_(F18)~A_(F)~C_(L)U_(F18)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F)~C_(F4)U_(L)~C_(F4)A_(F)~G_(F)G_(L)U_(F)~C_(F)~C_(L)UU_(F)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)P-U_(F)~U_(M)~G_(L)U_(F)~C_(F4)U_(L)~C_(F4)U_(F)~A_(F)G_(L)U_(F)~C_(F)~C_(L)UU_(F)~A_(F)~C_(L)U_(F)U_(F)~A_(F)~G_(F)

TABLE 8B Compositions of Matter Suitable for Administration to a Subjectwith or without a Protective Carrier and for Any Other use as Providedfor herein (5′-3′)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M)C_(F)~C_(M4)U~U_(M12)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(F)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M)C_(F)~C_(M4)U~U_(M3)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M)C_(F)~C_(M4)U~U_(M18)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M4)U_(F)~C_(M)U_(F12)~G_(M)G_(F)~U_(M)C_(F4)~C_(M)U~U_(M12)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M4)U_(F)~C_(M)U_(F3)~G_(M)G_(F)~U_(M)C_(F4)~C_(M)U~U_(M3)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M4)U_(F)~C_(M)U_(F18)~G_(M)G_(F)~U_(M)C_(F4)~C_(M)U~U_(M18)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M4)U_(F)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M)C_(F4)~C_(M4)U~U_(M12)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M4)U_(F)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M)C_(F4)~C_(M4)U~U_(M3)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M4)U_(F)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M)C_(F4)~C_(M4)U~U_(M18)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F)~C_(M)U_(F12)~G_(M)G_(F)~U_(M12)C_(F)~C_(M)U~U_(M12)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(F)~C_(M)U_(F3)~G_(M)G_(F)~U_(M3)C_(F)~C_(M)U~U_(M3)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F)~C_(M)U_(F18)~G_(M)G_(F)~U_(M18)C_(F)~C_(M)U~U_(M18)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F12)~C_(M)U_(F12)~G_(M)G_(F)~U_(M12)C_(F)~C_(M)U~U_(M12)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(F3)~C_(M)U_(F3)~G_(M)G_(F)~U_(M3)C_(F)~C_(M)U~U_(M3)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F18)~C_(M)U_(F18)~G_(M)G_(F)~U_(M18)C_(F)~C_(M)U~U_(M18)~A_(F)~C_(M)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F12)~C_(M)U_(F12)~G_(M)G_(F)~U_(M12)C_(F)~C_(M)U~U_(M12)~A_(F)~C_(M)~U_(F12)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(F3)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M)U~U_(M3)~A_(F)~C_(M)~U_(F3)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F18)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F)~C_(M)U~U_(M18)~A_(F)~C_(M)~U_(F18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(M)U~U_(M12)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(F)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M)U~U_(M3)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(M)U~U_(M18)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F12)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(M)U~U_(M12)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(L)F3~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M)U~U_(M3)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F18)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(M)U~U_(M18)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M)U_(F12)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(M)U~U_(M12)~A_(F)~C_(M4)~U_(F12)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M)U_(F3)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M)U~U_(M3)~A_(F)~C_(M4)~U_(F3)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M)U_(F18)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(M)U~U_(M18)~A_(F)~C_(M4)~U_(F18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M4)U_(F)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(M4)U~U_(M12)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M4)U_(F)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M4)U~U_(M3)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M4)U_(F)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(M4)U~U_(M18)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M4)U_(F12)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(M4)U~U_(M12)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M4)U_(F3)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M4)U~U_(M3)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M4)U_(F18)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(M4)U~U_(M18)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(M4)U_(F12)~C_(M4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(M4)U~U_(M12)~A_(F)~C_(M4)~U_(F12)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(M4)U_(F3)~C_(M4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(M4)U~U_(M3)~A_(F)~C_(M4)~U_(F3)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(M4)U_(F18)~C_(M4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(M4)U~U_(M18)~A_(F)~C_(M4)~U_(F18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F)~C_(M4)U_(F)~C_(M4)A_(F)~G_(M)G_(F)~U_(M)C_(F4)~C_(M4)U~U_(M)~A_(F)~C_(M4)~U_(F)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F)~C_(M4)U_(F)~C_(M4)A_(F)~A_(M)G_(F)~U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A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(L18)~C_(M4)U_(F18)~C_(M4)U_(L18)~G_(M)G_(F)~U_(M18)C_(L4)~C_(M4)U~U_(L18)~A_(F)~C_(M4)~U_(L18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(L)~C_(M4)U_(F)~C_(M4)A_(L)~G_(M)G_(F)~U_(M)C_(L4)~C_(M4)U~U_(L)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(L)~C_(M4)U_(F)~C_(M4)U_(L)~A_(M)G_(F)~U_(M)C_(L4)~C_(M4)U~U_(L)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F)~C_(L)U_(F)~C_(L)U_(F)~G_(M)G_(F)~U_(M)C_(F)~C_(L)U~U_(L)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M)C_(F)~C_(L4)U~U_(L12)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M)C_(F)~C_(L4)U~U_(L3)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M)C_(F)~C_(L4)U~U_(L18)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L4)U_(F)~C_(L)U_(F12)~G_(M)G_(F)~U_(M)C_(F4)~C_(L)U~U_(L12)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L4)U_(F)~C_(L)U_(F3)~G_(M)G_(F)~U_(M)C_(F4)~C_(L)U~U_(L3)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L4)U_(F)~C_(L)U_(F18)~G_(M)G_(F)~U_(M)C_(F4)~C_(L)U~U_(L18)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L4)U_(F)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M)C_(F4)~C_(L4)U~U_(L12)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L4)U_(F)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M)C_(F4)~C_(L4)U~U_(L3)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L4)U_(F)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M)C_(F4)~C_(L4)U~U_(L18)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F)~C_(L)U_(F12)~G_(M)G_(F)~U_(M12)C_(F)~C_(L)U~U_(L12)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F)~C_(L)U_(F3)~G_(M)G_(F)~U_(M3)C_(F)~C_(L)U~U_(L3)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F)~C_(L)U_(F18)~G_(M)G_(F)~U_(M18)C_(F)~C_(L)U~U_(L18)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F12)~C_(L)U_(F12)~G_(M)G_(F)~U_(M12)C_(F)~C_(L)U~U_(L12)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F3)~C_(L)U_(F3)~G_(M)G_(F)~U_(M3)C_(F)~C_(L)U~U_(L3)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F18)~C_(L)U_(F18)~G_(M)G_(F)~U_(M18)C_(F)~C_(L)U~U_(L18)~A_(F)~C_(M)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F12)~C_(L)U_(F12)~G_(M)G_(F)~U_(M12)C_(F)~C_(L)U~U_(L12)~A_(F)~C_(M)~U_(L12)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F3)~C_(L)U_(F3)~G_(M)G_(F)~U_(M3)C_(F)~C_(L)U~U_(L3)~A_(F)~C_(M)~U_(L3)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F18)~C_(L)U_(F18)~G_(M)G_(F)~U_(M18)C_(F)~C_(L)U~U_(L18)~A_(F)~C_(M)~U_(L18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(L)U~U_(L12)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(L)U~U_(L3)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(L)U~U_(L18)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F12)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(L)U~U_(L12)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F3)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(L)U~U_(L3)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F18)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(L)U~U_(L18)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L)U_(F12)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(F)U~U_(F12)~A_(F)~C_(M4)~U_(F12)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L)U_(F3)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(L)U~U_(L3)~A_(F)~C_(M4)~U_(L3)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L)U_(F18)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(L)U~U_(L18)~A_(F)~C_(M4)~U_(L18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L4)U_(F)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(L4)U~U_(L12)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L4)U_(F)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(L4)U~U_(L3)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L4)U_(F)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(L4)U~U_(L18)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L4)U_(F12)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(L4)U~U_(L12)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L4)U_(F3)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(L4)U~U_(L3)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L4)U_(F18)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(L4)U~U_(L18)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F12)~C_(L4)U_(F12)~C_(L4)U_(F12)~G_(M)G_(F)~U_(M12)C_(F4)~C_(L4)U~U_(L12)~A_(F)~C_(M4)~U_(L12)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F3)~C_(L4)U_(F3)~C_(L4)U_(F3)~G_(M)G_(F)~U_(M3)C_(F4)~C_(L4)U~U_(L3)~A_(F)~C_(M4)~U_(L3)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F18)~C_(L4)U_(F18)~C_(L4)U_(F18)~G_(M)G_(F)~U_(M18)C_(F4)~C_(L4)U~U_(L18)~A_(F)~C_(M4)~U_(L18)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F)~C_(L4)U_(F)~C_(L4)A_(F)~G_(M)G_(F)~U_(M)C_(F4)~C_(L4)U~U_(L)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)P-U_(M)~U_(F)~G_(M)U_(F)~C_(L4)U_(F)~C_(L4)U_(F)~A_(M)G_(F)~U_(M)C_(F4)~C_(L4)U~U_(L)~A_(F)~C_(M4)~U_(L)~U_(M)~A_(L)~A_(L)~G_(M)

Table 9 Examples of Murine/Human PTEN ags-siRNA Compositions A.Murine/Human PTEN Antisense Sequence:

UGAACAUUGGAAUAGUUUC

Lima et al. (Cell 150: 883-94, 2012) used this sequence to generatessRNAi compounds against human/murine PTEN including the following:

5′-VP-T_(moe)~G_(F)~A_(M)A_(F)~C_(M)A_(F)~U_(M)U_(F)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F)~U_(M)~U_(F)~C_(M)~A_(moe)~A_(moe)

Any of the 5′-end nucleosides (P-U_(M)) shown in the examples of agsRNAicompounds in Table 9 can be replaced with any of those provided forherein including one of the 5′end nucleosides selected from the groupconsisting of: P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-A_(F), P-A_(M), P-A_(N), P-A_(L), P-A_(Z), P-A_(H), P-A_(B), P-A_(K),P-A_(Q), P-A_(S), P-A_(T), P-A_(W), P-A_(V), P-U_(F), P-U_(M), P-U_(L),P-U_(Z), P-U_(H), P-U_(H), P-U_(K), P-U_(Q), P-U_(S), P-U_(T), P-U_(W),P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 9 with an L modification(s) found in oneor more positions 2-19 can have any given L or set of Ls replaced withany of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the compounds in Table 9 can any of those units and linkagesprovided for herein for overhang precursors.

B. Examples of agsRNAi Compounds:

Compositions of Matter Suitable for Administration to a Subject with orwithout a Protective Carrier and for Any Other use as Provided forHerein (5′-3′)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F3)~U_(M3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M3)A_(F)~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F12)~U_(M12)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M12)A_(F)~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F18)~U_(M18)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)A_(F)~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F3)~U_(M3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M3)A_(F)~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M3)A_(F)~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F12)~U_(M12)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M12)A_(F)~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M12)A_(F)~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)A_(F)~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A_(F)~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)A_(F)~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F3)~U_(M3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M3)A~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F12)~U_(M12)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M12)A~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F18)~U_(M18)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)A~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F3)~U_(M3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M3)A~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(M)G_(F)~A_(M)A_(F)~U_(M3)A~G_(M)~U_(F3)~U_(M3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F12)~U_(M12)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M12)A~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(M)G_(F)~A_(M)A_(F)~U_(M12)A~G_(M)~U_(F12)~U_(M12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M)A~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)A~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(F2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(M)G_(F)~A_(M)A_(F)~U_(M18)A~G_(M)~U_(F18)~U_(M18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M)A_(L)~U_(M)U_(F)~G_(L)G_(F)~A_(M)A_(L)~U_(M)A_(F)~G_(L)~U_(F)~U_(M)~U_(L)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M)A_(L)~U_(M)U_(F)~G_(L)G_(F)~A_(M)A_(L)~U_(M)A~G_(L)~U_(F)~U_(M)~U_(L)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(L)~U_(M)A_(F)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F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L3)A_(F)~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F12)~U_(L12)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L12)A_(F)~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F18)~U_(L18)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L18)A_(F)~G_(M)~U_(L18)~U_(M18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F3)~U_(L3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L3)A_(F)~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L3)A_(F)~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F12)~U_(L12)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L12)A_(F)~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L12)A_(F)~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L18)A_(F)~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A_(F)~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L18)A_(F)~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F3)~U_(L3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L3)A~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F12)~U_(L12)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L12)A~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F18)~U_(L18)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L18)A~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F3)~U_(L3)~U_(F)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L3)A~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M3)U_(F3)~G_(L)G_(F)~A_(M)A_(F)~U_(L3)A~G_(M)~U_(F3)~U_(L3)~U_(F3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F12)~U_(L12)~U_(F3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L12)A~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M12)U_(F12)~G_(L)G_(F)~A_(M)A_(F)~U_(L12)A~G_(M)~U_(F12)~U_(L12)~U_(F12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M4)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L18)A~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L)A~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(M)A_(L2)~C_(M)A_(F)~U_(M18)U_(F18)~G_(L)G_(F)~A_(M)A_(F)~U_(L18)A~G_(M)~U_(F18)~U_(L18)~U_(F18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M)A_(L)~U_(M)U_(F)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F)~U_(M)~U_(L)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M)A_(L)~U_(M)U_(F)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F)~U_(M)~U_(L)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F3)~U_(M3)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M3)A_(F)~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F12)~U_(M12)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M12)A_(F)~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F18)~U_(M18)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M18)A_(F)~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F3)~U_(M3)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M3)A_(F)~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M3)A_(F)~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F12)~U_(M12)~U_(L3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M12)A_(F)~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M12)A_(F)~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M18)A_(F)~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A_(F)~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M18)A_(F)~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F3)~U_(M3)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M3)A~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F12)~U_(M12)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M12)A~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M18)U_(P18)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F18)~U_(M18)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F)~C_(M4)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M18)A~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F3)~U_(M3)~U_(L)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M3)A~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M3)U_(F3)~G_(M)G_(L)~A_(M)A_(F)~U_(M3)A~G_(L)~U_(F3)~U_(M3)~U_(L3)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M12)U_(P12)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F12)~U_(M12)~U_(L3)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M12)A~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M12)U_(F12)~G_(M)G_(L)~A_(M)A_(F)~U_(M12)A~G_(L)~U_(F12)~U_(M12)~U_(L12)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M18)U_(P18)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M4)A_(L)~U_(M18)U_(P18)~G_(M)G_(L)~A_(M)A_(F)~U_(M18)A~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M4)~A_(F)~G_(M)P-U_(M)~G_(F)~A₁A_(F2)~C_(M)A_(L)~U_(M18)U_(F18)~G_(M)G_(L)~A_(M)A_(F)~U_(M)A~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M)~A_(F)~G_(M)P-U_(M)~G_(F)~A_(L)A_(F2)~C_(M)A_(L)~U_(M18)U_(P18)~G_(M)G_(L)~A_(M)A_(F)~U_(M18)A~G_(L)~U_(F18)~U_(M18)~U_(L18)~C_(M)~A_(F)~G_(M)

Table 10 Examples of Murine/Human PTEN ags-siRNA Compositions A.Murine/Human PTEN Antisense Sequence:

UUAUCUAUAAUGAUCAGGU

Lima et al. (Cell 150: 883-94, 2012) used this sequence to generatessRNAi compounds against human/murine PTEN including the following:

5′-VP-T_(moe)~U_(F)~A_(M)U_(F)~C_(M)U_(F)~A_(M)U_(F)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(M)~A_(F)~G_(M)~G_(F)~U_(M)~A_(moe)~A_(moe)B. Examples of Application of AGSD Rules to these Compounds:

Any of the 5′-end nucleosides (P-U_(M)) shown in the examples of agsRNAicompounds in Table 10 can be replaced with any of those provided forherein including one of the 5′end nucleosides selected from the groupconsisting of: P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z), P-C_(H), P-C_(B), P-C_(K),P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O), P-U_(F), P-U_(M),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 10 with an L modification(s) found inone or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the compounds in Table 10 can any of those units and linkagesprovided for herein for overhang precursors.

B. Examples of agsRNAi Compounds:

Compositions of Matter Suitable for Administration to a Subject with orwithout a Protective Carrier and for Any Other use as Provided forHerein 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(M4)~A_(L)~G_(F)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M3)~C_(F4)U_(M3)~A_(L)U_(F3)~A_(L)A_(F)~U_(M)G_(F)~A_(L)U_(F3)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M3)~C_(F4)U_(M3)~A_(L)U_(F3)~A_(L)A_(F)~U_(M3)G_(F)~A_(L)U_(F3)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M12)~C_(F)U_(M12)~A_(L)U_(F12)~A_(L)A_(F)~U_(M)G_(F)~A_(L)U_(F)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M12)~C_(F4)U_(M12)~A_(L)U_(F12)~A_(L)A_(F)~U_(M)G_(F)~A_(L)U_(F12)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M12)~C_(F4)U_(M12)~A_(L)U_(F12)~A_(L)A_(F)~U_(M12)G_(F)~A_(L)U_(F12)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M18)~C_(F)U_(M18)~A_(L)U_(F18)~A_(L)A_(F)~U_(M)G_(F)~A_(L)U_(F)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M18)~C_(F4)U_(M18)~A_(L)U_(F18)~A_(L)A_(F)~U_(M)G_(F)~A_(L)U_(F18)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(L)U_(M18)~C_(F4)U_(M18)~A_(L)U_(F18)~A_(L)A_(F)~U_(M18)G_(F)~A_(L)U_(F18)~C_(M4)~A_(L)~G_(F)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~A_(M)U_(F)~C_(L)U_(F)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L)~A_(F)~G_(M)~G_(L)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~A_(M)U_(F)~C_(L)U_(F)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M)~C_(L)U_(M)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L)~A_(F)~G_(M)~G_(L)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F3)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M3)G_(F)~A_(M)U_(F3)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F12)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M12)G_(F)~A_(M)U_(F12)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F18)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U_(F18)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M3)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(F)~U_(M3)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M12)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(F)~U_(M12)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(F)~U_(M)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(F)~U_(M18)G_(F)~A_(M)U~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M3)~C_(L)U_(M3)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M3)~C_(L)U_(M3)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F3)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M3)~C_(L)U_(M3)~A_(F)U_(L)~A_(F)A_(F)~U_(M3)G_(F)~A_(M)U_(F3)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M12)~C_(L)U_(M12)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M12)~C_(L)U_(M12)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F12)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M12)~C_(L)U_(M12)~A_(F)U_(L)~A_(F)A_(F)~U_(M12)G_(F)~A_(M)U_(F12)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M18)~C_(L)U_(M18)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M18)~C_(L)U_(M18)~A_(F)U_(L)~A_(F)A_(F)~U_(M)G_(F)~A_(M)U_(F18)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(M)~A_(F)U_(M18)~C_(L)U_(M18)~A_(F)U_(L)~A_(F)A_(F)~U_(M18)G_(F)~A_(M)U_(F18)~C_(L4)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~A_(M)U_(F)~C_(L)U_(F)~A_(M)U_(L)~A_(M)A_(L)~U_(M)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M) _(A)_(L)~U_(M)G_(F)~A_(M)U ~C_(L)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~A_(M)U_(F12)~C_(L)U_(F12)~A_(M)U_(L)~A_(M)A_(L)~U_(M12)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(L)~U_(M)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~A_(M)U_(F18)~C_(L)U_(F18)~A_(M)U_(L)~A_(M)A_(L)~U_(M18)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(L)~U_(M)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~A_(M)U_(F3)~C_(L)U_(F3)~A_(M)U_(L)~A_(M)A_(L)~U_(M3)G_(F)~A_(M)U~C_(L)~A_(F)~G_(M)~G_(L)~U_(M3)~A_(F)~G_(M)

Table 11 Examples of Murine Factor VII ags-siRNA Compositions A. MurineFactor VII Antisense Sequence:

UUAAGACUUGAGAUGAUCC

Lima et al. (Cell 150: 883-94, 2012) used this sequence to generatessRNAi compounds against human/murine PTEN including the following:

5′-VP-T_(moe)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M)~C_(F)~C_(M)~A_(moe)~A_(moe)

With the 5′-VP, T and 2′-MOE modifications removed and replaced by P, Uand 2′-O-methyl:

P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M)~C_(F)~C_(M)~A_(M)~A_(M)

Any of the 5′-end nucleosides (P-U_(M)) shown in the examples of agsRNAicompounds in Table 11 can be replaced with any of those provided forherein including one of the 5′end nucleosides selected from the groupconsisting of: P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z), P-C_(H), P-C_(B), P-C_(K),P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O), P-U_(F), P-U_(M),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 11 with an L modification(s) found inone or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the compounds in Table 11 can any of those units and linkagesprovided for herein for overhang precursors.

B. Examples of Application of AGSD Rules to this Compound:

Compositions of Matter Suitable for Administration to a Subject with orwithout a Protective Carrier and for Any Other use as Provided forHerein (5′-3′)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F3)~G_(M)~A_(F)~U_(M3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F3)~G_(M)~A_(F)~U_(M3)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F3)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U_(F3)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F3)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F3)~G_(M)~A_(F)~U_(M3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U_(F3)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U_(F3)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M3)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F3)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F3)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F3)~U_(M3)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F12)~G_(M)~A_(F)~U_(M12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F12)~G_(M)~A_(F)~U_(M12)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U_(F12)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F12)~G_(M)~A_(F)~U_(M12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U_(F12)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U_(F12)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M12)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(M)U~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F18)~G_(M)~A_(F)~U_(M18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F18)~G_(M)~A_(F)~U_(M18)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(M)U_(F18)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~C_(M)U_(F)~U_(M18)G_(F)~A_(M)G_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(M)U_(F18)~G_(M)~A_(F)~U_(M18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F)~U_(M18)G_(F)~A_(M)G_(F)~A_(M)U_(F18)~G_(M)~A_(F)~U_(M)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~C_(M4)U_(F18)~U_(M1s)G_(F)~A_(M)G_(F)~A_(M)U_(F18)~G_(M)~A_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F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F)~U_(M12)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M12)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(L)U_(F18)~G_(M)~A_(L)~U_(M18)~C_(F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(L)U_(F18)~G_(M)~A_(L)~U_(M18)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U_(F18)~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U_(F)~G_(M)~A_(L)~U_(M18)~C_(F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M)U_(F)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U_(F)~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(L)U_(F18)~G_(M)~A_(L)~U_(M18)~C_(F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U_(F18)~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U_(F18)~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M18)~C_(F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M18)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M18)~C_(F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M)U_(F)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M18)~C_(F)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M18)G_(F)~A_(M)G_(F)~A_(L)U~G_(M)~A_(L)~U_(M)~C_(F4)~C_(L4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L)~C_(F)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F3)~G_(L)~A_(F)~U_(L3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F3)~G_(L)~A_(F)~U_(L3)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F3)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U_(F3)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F3)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F3)~G_(L)~A_(F)~U_(L3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U_(F3)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U_(F3)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L3)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F3)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F3)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L3)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F3)~U_(M3)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F12)~G_(L)~A_(F)~U_(L12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F12)~G_(L)~A_(F)~U_(L12)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F12)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U_(F12)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F12)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F12)~G_(L)~A_(F)~U_(L12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U_(F12)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U_(F12)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L12)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F12)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F12)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L12)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F12)~U_(M12)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F18)~G_(L)~A_(F)~U_(L18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F18)~G_(L)~A_(F)~U_(L18)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U_(F18)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U_(F18)~G_(L)~A_(F)~U_(L18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U_(F18)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U_(F18)~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L18)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F18)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M)U_(F)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L18)~C_(F)~C_(M4)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M)~A_(M)~A_(M)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~C_(M4)U_(F18)~U_(M18)G_(F)~A_(L)G_(F)~A_(L)U~G_(L)~A_(F)~U_(L)~C_(F4)~C_(M4)~A_(M)~A_(M)

Table 12 Examples of Murine APO-CIII ags-siRNA Compositions A. MurineApo-CIII Antisense Sequence:

UAUGAGAACAUACUUUCCC

Lima et al. (Cell 150: 883-94, 2012) used this sequence to generatessRNAi compounds against human/murine PTEN including the following:

5′-VP~T_(moe)~A_(F)~T_(M)G_(F)~A_(M)G_(F)~A_(M)A_(F)~C_(M)A_(F)~T_(M)A_(F)~C_(M)T_(F)~T_(M)~T_(F)~C_(M)~C_(F)~C_(M)~A_(moe)~A_(moe)

With the 5′-VP, T and 2′-MOE Modifications Removed and Replaced by P, Uand 2′-O-methyl:

P-U_(M)~A_(F)~U_(M)G_(F)~A_(M)G_(F)~A_(M)A_(F)~C_(M)A_(F)~U_(M)A_(F)~C_(M)U_(F)~U_(M)~U_(F)~C_(M)~C_(F)~C_(M)~A_(M)~A_(M)

Any of the 5′-end nucleosides (P-U_(M)) shown in the examples of agsRNAicompounds in Table 12 can be replaced with any of those provided forherein including one of the 5′end nucleosides selected from the groupconsisting of: P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-A_(F), P-A_(M), P-A_(N), P-A_(L), P-A_(Z), P-A_(H), P-A_(B), P-A_(K),P-A_(Q), P-A_(S), P-A_(T), P-A_(W), P-A_(V), P-A_(O), P-U_(F), P-U_(M),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 12 with an L modification(s) found inone or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the compounds in Table 12 can any of those units and linkagesprovided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

Compositions of Matter Suitable for Administration to a Subject with orwithout a Protective Carrier and for Any Other use as Provided forHerein 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~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L)A_(F)~U_(M)A_(F)~C_(M)U~U_(L)~U_(F12)~C_(M)~C_(L4)~C_(M)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M)A_(F)~C_(M4)U~U_(L12)~U_(F)~C_(M4)~C_(L)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M12)A_(F)~C_(M4)U~U_(L12)~U_(F12)~C_(M4)~C_(L4)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L)A_(F)~U_(M)A_(F)~C_(M)U~U_(L)~U_(F12)~C_(M)~C_(L4)~C_(M)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L12)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M)A_(F)~C_(M4)U~U_(L12)~U_(F)~C_(M4)~C_(L)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L12)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M12)A_(F)~C_(M4)U~U_(L12)~U_(F12)~C_(M4)~C_(L4)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L12)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L)A_(F)~U_(M)A_(F)~C_(M)U~U_(L)~U_(F12)~C_(M)~C_(L4)~C_(M)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L12)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M)A_(F)~C_(M4)U~U_(L12)~U_(F)~C_(M4)~C_(L)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L12)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M12)A_(F)~C_(M4)U~U_(L12)~U_(F12)~C_(M4)~C_(L4)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L)A_(F)~U_(M)A_(F)~C_(M)U~U_(L)~U_(F18)~C_(M)~C_(L4)~C_(M)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M)A_(F)~C_(M4)U~U_(L18)~U_(F)~C_(M4)~C_(L)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M18)A_(F)~C_(M4)U~U_(L18)~U_(F18)~C_(M4)~C_(L4)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L)A_(F)~U_(M)A_(F)~C_(M)U~U_(L)~U_(F18)~C_(M)~C_(L4)~C_(M)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L18)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M)A_(F)~C_(M4)U~U_(L18)~U_(F)~C_(M4)~C_(L)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L18)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M18)A_(F)~C_(M4)U~U_(L18)~U_(F18)~C_(M4)~C_(L4)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L18)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L)A_(F)~U_(M)A_(F)~C_(M)U~U_(L)~U_(F18)~C_(M)~C_(L4)~C_(M)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L18)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M)A_(F)~C_(M4)U~U_(L18)~U_(F)~C_(M4)~C_(L)~C_(M4)~A_(M)~A_(M)P-U_(M)~A_(F)~U_(L18)G_(F)~A_(L)G_(F)~A_(M)A_(F)~C_(L4)A_(F)~U_(M18)A_(F)~C_(M4)U~U_(L18)~U_(F18)~C_(M4)~C_(L4)~C_(M4)~A_(M)~A_(M)

Table 13 Examples of Murine SSB ags-siRNA Compositions A. Murine SSBAntisense Sequence:

ACAUUAAAGUCUGUUGUCA

Haringsma et al. (Nucleic Acids Res 40: 4125-36, 2012) used thissequence to generate ssRNAi compounds against murine SSB target site 386including the following:

P-A_(F)C_(F)A_(F)U_(F)U_(F)A_(F)A_(F)A_(F)G_(F)U_(F)C_(F)U_(F)G_(F)U_(F)U_(F)G_(F)U_(F)C_(F)A_(F)U_(M)U_(M)

Any of the 5′-end nucleosides (P-A_(F) or P-A_(M)) shown in the examplesof agsRNAi compounds in Tables 13A and 13B can be replaced with any ofthose provided for herein including one of the 5′end nucleosidesselected from the group consisting of: P-G_(F), P-G_(M), P-G_(N),P-G_(L), P-G_(Z), P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T),P-G_(W), P-G_(V), P-G_(O), P-A_(F), P-A_(M), P-A_(N), P-A_(L), P-A_(Z),P-A_(H), P-A_(B), P-A_(K), P-A_(Q), P-A_(S), P-A_(T), P-A_(W), P-A_(V),P-A_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K), 5′-VP-U_(Q),5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E), 5′-VP-T_(Z),5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Tables 13A and 13B with an L modification(s)found in one or more positions 2-19 can have any given L or set of Lsreplaced with any of those sugar, sugar analogs or sugar substitutesprovided for herein for positions 2-19 including one or more of thoseindependently selected from the group consisting of: S, J, W, V, Q, Y,O, T and cet (i.e., if multiple Ls are replaced the selectedreplacements do not all have to be the same sugar, sugar analog or sugarsubstitute).

Any of the compounds in Tables 13A and 13B can any of those units andlinkages provided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

TABLE 13A Compositions of Matter Suitable for Use in vitro or in aSubject with a Protective Carrier 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F18)C_(F)U_(L18)G_(F)UU_(L18)G_(F)U_(L18)C_(F4)A_(F)A_(F)G_(M)P-A_(F)C_(F)A_(F)U_(L18)U_(F18)A_(F)A_(F)A_(L)G_(F)U_(F)C_(F4)U_(L18)G_(F)UU_(L18)G_(F)U_(L18)C_(F)A_(F)A_(F)G_(M)P-A_(F)C_(F4)A_(F)U_(L18)U_(F18)A_(F)A_(F)A_(L)G_(F)U_(F)C_(F)U_(L18)G_(F)UU_(L18)G_(F)U_(L18)C_(F4)A_(F)A_(F)G_(M)P-A_(F)C_(F)A_(F)U_(L18)U_(F18)A_(F)A_(F)A_(L)G_(F)U_(F18)C_(F4)U_(L18)G_(F)UU_(L18)G_(F)U_(L18)C_(F)A_(F)A_(F)G_(M)P-A_(F)C_(F4)A_(F)U_(L18)U_(F18)A_(F)A_(F)A_(L)G_(F)U_(F18)C_(F4)U_(L18)G_(F)UU_(L18)G_(F)U_(L18)C_(F4)A_(F)A_(F)G_(M)

TABLE 13B Compositions of Matter Suitable for Administration to aSubject with or without a Protective Carrier and for Any Other use asProvided for Herein (5′-3′)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U_(F)~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U_(F)~U_(M3)~G_(F)~U_(M3)~C_(F4-)A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F3)~C_(M)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F-)A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F3)~C_(M)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M4)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F3)~C_(M4)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F3)~C_(M4)U_(F3)~G_(M)U_(F3)~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F12)~G_(M)U_(F)~U_(M12)~G_(F)~U_(M12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F12)~G_(M)U_(F)~U_(M12)~G_(F)~U_(M12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F12)~C_(M)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F12)~C_(M)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M4)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F12)~C_(M4)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F12)~U_(M12)A_(F)~A_(M)A_(F)~G_(M)U_(F12)~C_(M4)U_(F12)~G_(M)U_(F12)~U_(M12)~G_(F)~U_(M12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F18)~G_(M)U_(F)~U_(M18)~G_(F)~U_(M18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F18)~G_(M)U_(F)~U_(M18)~G_(F)~U_(M18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F18)~C_(M)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F18)~C_(M)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M4)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F18)~C_(M4)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F18)~U_(M18)A_(F)~A_(M)A_(F)~G_(M)U_(F18)~C_(M4)U_(F18)~G_(M)U_(F18)~U_(M18)~G_(F)~U_(M18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F3)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F3)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M4)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(F3)~U_(M3)A_(F)~A_(M)A_(F)~G_(M)U_(F)~C_(M)U_(F3)~G_(M)U~U_(M3)~G_(F)~U_(M3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(F3)~U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(M12)A_(F)~A_(L)A_(F)~G_(L)U_(F12)~C_(M)U_(F12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F12)~U_(M12)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M4)U_(F12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F12)~U_(M12)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M)U_(F12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(L)U_(F12)~U_(M12)A_(F)~A_(L)A_(F)~G_(L)U_(F12)~C_(M4)U_(F12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F12)~U_(M12)A_(F)~A_(L)A_(F)~G_(L)U_(F12)~C_(M4)U_(F12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F18)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F18)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M4)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F)~C_(M)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F18)~C_(M4)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(L)U_(F18)~U_(M18)A_(F)~A_(L)A_(F)~G_(L)U_(F18)~C_(M4)U_(F18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L)~U_(M)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L)~G_(M)U_(F)~U_(L)~G_(F)~U_(M)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L)~U_(M)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L)~G_(M)U~U_(L)~G_(F)~U_(L)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U_(F)~U_(L3)~G_(F)~U_(M3)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U_(F)~U_(L3)~G_(F)~U_(M3)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M4)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M4)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M4)U_(L3)~G_(M)U_(F3)~U_(L3)~G_(F)~U_(M3)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U_(F)~U_(L12)~G_(F)~U_(M12)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U_(F)~U_(L12)~G_(F)~U_(M12)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U_(F)~U_(L12)~G_(F)~U_(M12)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U_(F)~U_(L12)~G_(F)~U_(M12)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M)U_(L12)~G_(M)U_(F12)~U_(L12)~G_(F)~U_(M12)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M)U_(L12)~G_(M)U_(F12)~U_(L12)~G_(F)~U_(M12)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M4)U_(L12)~G_(M)U_(F12)~U_(L12)~G_(F)~U_(M12)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U_(F12)~U_(L12)~G_(F)~U_(M12)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M4)U_(L12)~G_(M)U_(F12)~U_(L12)~G_(F)~U_(M12)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M4)U_(L12)~G_(M)U_(F12)~U_(L12)~G_(F)~U_(M12)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U_(F)~U_(L18)~G_(F)~U_(M18)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U_(F)~U_(L18)~G_(F)~U_(M18)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M4)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M4)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M4)U_(L18)~G_(M)U_(F18)~U_(L18)~G_(F)~U_(M18)~C_(L4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M4)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M4)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L3)~U_(M3)A_(F)~A_(M)A_(L)~G_(M)U_(F3)~C_(M4)U_(L3)~G_(M)U~U_(L3)~G_(F)~U_(L3)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M4)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M4)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L12)~U_(M12)A_(F)~A_(M)A_(L)~G_(M)U_(F12)~C_(M4)U_(L12)~G_(M)U~U_(L12)~G_(F)~U_(L12)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M4)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F)~C_(M)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M4)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F)~A_(M)~A_(F)~G_(M)P-A_(M)~C_(F4)~A_(M)U_(L18)~U_(M18)A_(F)~A_(M)A_(L)~G_(M)U_(F18)~C_(M4)U_(L18)~G_(M)U~U_(L18)~G_(F)~U_(L18)~C_(F4)~A_(M)~A_(F)~G_(M)

Table 14 Examples of Murine SSB ags-siRNA Compositions A. Murine SSBAntisense Sequence:

UUUUAUUUCACCAUGAUUU

Haringsma et al. (Nucleic Acids Res 40: 4125-36, 2012) used thissequence to generate ssRNAi compounds against murine SSB target site 963including the following:

P-U_(F)U_(F)U_(F)U_(F)A_(F)U_(F)U_(F)U_(F)C_(F)A_(F)C_(F)C_(F)A_(F)U_(F)G_(F)A_(F)U_(F)U_(F)U_(F)U_(M)U_(M)

Any of the 5′-end nucleosides (P-U_(F) or P-U_(M)) shown in the examplesof agsRNAi compounds in Tables 14A and 14B can be replaced with any ofthose provided for herein including one of the 5′end nucleosidesselected from the group consisting of: P-G_(F), P-G_(M), P-G_(N),P-G_(L), P-G_(Z), P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T),P-G_(W), P-G_(V), P-G_(O), P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z),P-C_(H), P-C_(B), P-C_(K), P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V),P-C_(O), P-U_(F), P-U_(M), P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K),P-U_(Q), P-U_(S), P-U_(T), P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H),5′-VP-U_(Z), 5′-VP-U_(K), 5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe),5′-VP-T_(E), 5′-VP-U_(E), 5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and5′-VP-T_(B).

Any of the nucleosides in Tables 14A and 14B with an L modification(s)found in one or more positions 2-19 can have any given L or set of Lsreplaced with any of those sugar, sugar analogs or sugar substitutesprovided for herein for positions 2-19 including one or more of thoseindependently selected from the group consisting of: S, J, W, V, Q, Y,O, T and cet (i.e., if multiple Ls are replaced the selectedreplacements do not all have to be the same sugar, sugar analog or sugarsubstitute).

Any of the compounds in Tables 14A and 14B can any of those units andlinkages provided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

TABLE 14A Compositions of Matter Suitable for Use in vitro or in aSubject with a Protective Carrier 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(F18)U_(F18)U_(L18)C_(F)A_(F)C_(F)C_(L)A_(F)U_(F)G_(F)A_(F)U_(L18)U_(F18)U_(L18)U_(M)U_(M)P-U_(F)U_(F18)U_(F18)U_(F18)A_(L)U_(F18)U_(F18)U_(L18)C_(F4)A_(F)C_(F)C_(L4)A_(F)U_(F)G_(F)A_(F)U_(L18)U_(F18)U_(L18)U_(M)U_(M)P-U_(F)U_(F)U_(F)U_(F3)A_(L)U_(F3)U_(F)U_(L)C_(F4)A_(F)C_(F)C_(L4)A_(F)UG_(F)A_(F)U_(L3)U_(F)U_(L)U_(M)U_(M)P-U_(F)U_(F)U_(F3)U_(F3)A_(L)U_(F3)U_(F3)U_(L)C_(F4)A_(F)C_(F)C_(L)A_(F)UG_(F)A_(F)U_(L3)U_(F3)U_(L)U_(M)U_(M)P-U_(F)U_(F3)U_(F3)U_(F3)A_(L)U_(F3)U_(F3)U_(L3)C_(F)A_(F)C_(F)C_(L)A_(F)UG_(F)A_(F)U_(L3)U_(F3)U_(L3)U_(M)U_(M)P-U_(F)U_(F3)U_(F3)U_(F3)A_(L)U_(F3)U_(F3)U_(L3)C_(F4)A_(F)C_(F)C_(L4)A_(F)UG_(F)A_(F)U_(L3)U_(F3)U_(L3)U_(M)U_(M)P-U_(F)U_(F)U_(F)U_(F12)A_(L)U_(F12)U_(F)U_(L)C_(F4)A_(F)C_(F)C_(L4)A_(F)UG_(F)A_(F)U_(L12)U_(F)U_(L)U_(M)U_(M)P-U_(F)U_(F)U_(F12)U_(F12)A_(L)U_(F12)U_(F12)U_(L)C_(F4)A_(F)C_(F)C_(L)A_(F)UG_(F)A_(F)U_(L12)U_(F12)U_(L)U_(M)U_(M)P-U_(F)U_(F12)U_(F12)U_(F12)A_(L)U_(F12)U_(F12)U_(L12)C_(F)A_(F)C_(F)C_(L)A_(F)UG_(F)A_(F)U_(L12)U_(F12)U_(L12)U_(M)U_(M)P-U_(F)U_(F12)U_(F12)U_(F12)A_(L)U_(F12)U_(F12)U_(L12)C_(F4)A_(F)C_(F)C_(L4)A_(F)UG_(F)A_(F)U_(L12)U_(F12)U_(L12)U_(M)U_(M)P-U_(F)U_(F)U_(F)U_(F18)A_(L)U_(F18)U_(F)U_(L)C_(F4)A_(F)C_(F)C_(L4)A_(F)UG_(F)A_(F)U_(L18)U_(F)U_(L)U_(M)U_(M)P-U_(F)U_(F)U_(F18)U_(F18)A_(L)U_(F18)U_(F18)U_(L)C_(F4)A_(F)C_(F)C_(L)A_(F)UG_(F)A_(F)U_(L18)U_(F18)U_(L)U_(M)U_(M)P-U_(F)U_(F18)U_(F18)U_(F18)A_(L)U_(F18)U_(F18)U_(L18)C_(F)A_(F)C_(F)C_(L)A_(F)UG_(F)A_(F)U_(L18)U_(F18)U_(L18)U_(M)U_(M)P-U_(F)U_(F18)U_(F18)U_(F18)A_(L)U_(F18)U_(F18)U_(L18)C_(F4)A_(F)C_(F)C_(L4)A_(F)UG_(F)A_(F)U_(L18)U_(F18)U_(L18)U_(M)U_(M)

TABLE 14B Compositions of Matter Suitable for Administration to aSubject with or without a Protective Carrier and for Any Other use asProvided for Herein (5′-3′)P-U_(M)~U_(F)~U_(M)U_(F3)~A_(M)U_(F3)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(M)~A_(F)~U_(M3)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M3)U_(F3)~A_(M)U_(F3)~U_(M3)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M3)~U_(F3)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(M)U_(F3)~U_(M3)U_(F3)~C_(M)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(M)U_(F3)~U_(M3)U_(F3)~C_(M3)A_(F)~C_(M)C_(F3)~A_(M)U_(F)~G_(M)~A_(F)~U_(M3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F12)~A_(M)U_(F12)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(M)~A_(F)~U_(M12)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M12)U_(F12)~A_(M)U_(F12)~U_(M12)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(M)~A_(F)~U_(M12)~U_(F12)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(M)U_(F12)~U_(M12)U_(F12)~C_(M)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(M)~A_(F)~U_(M12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(M)U_(F12)~U_(M12)U_(F12)~C_(M12)A_(F)~C_(M)C_(F12)~A_(M)U_(F)~G_(M)~A_(F)~U_(M12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F12)~A_(M)U_(F18)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(M)~A_(F)~U_(M18)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M18)U_(F18)~A_(M)U_(F18)~U_(M18)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M18)~U_(F18)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(M)U_(F18)~U_(M18)U_(F18)~C_(M)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(M)~A_(F)~U_(M18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(M)U_(F18)~U_(M18)U_(F18)~C_(M18)A_(F)~C_(M)C_(F18)~A_(M)U_(F)~G_(M)~A_(F)~U_(M18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F3)~A_(M)U_(F3)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(M)~A_(F)~U_(M3)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M3)U_(F3)~A_(M)U_(F3)~U_(M3)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(M)U~G_(M)~A_(F)~U_(M3)~U_(F3)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(M)U_(F3)~U_(M3)U_(F3)~C_(M)A_(F)~C_(M)C_(F)~A_(M)U~G_(M)~A_(F)~U_(M3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(M)U_(F3)~U_(M3)U_(F3)~C_(M3)A_(F)~C_(M)C_(F3)~A_(M)U~G_(M)~A_(F)~U_(M3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F12)~A_(M)U_(F12)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(M)~A_(F)~U_(M12)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M12)U_(F12)~A_(M)U_(F12)~U_(M12)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(M)~A_(F)~U_(M12)~U_(F12)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(M)U_(F12)~U_(M12)U_(F12)~C_(M)A_(F)~C_(M)C_(F4)~A_(M)U~G_(M)~A_(F)~U_(M12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(M)U_(F12)~U_(M12)U_(F12)~C_(M12)A_(F)~C_(M)C_(F12)~A_(M)U~G_(M)~A_(F)~U_(M12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F12)~A_(M)U_(F18)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(M)~A_(F)~U_(M18)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M18)U_(F18)~A_(M)U_(F18)~U_(M18)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(M)U~G_(M)~A_(F)~U_(M18)~U_(F18)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(M)U_(F18)~U_(M18)U_(F18)~C_(M)A_(F)~C_(M)C_(F)~A_(M)U~G_(M)~A_(F)~U_(M18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(M)U_(F18)~U_(M18)U_(F18)~C_(M18)A_(F)~C_(M)C_(F18)~A_(M)U~G_(M)~A_(F)~U_(M18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F)~A_(L)U_(F)~U_(M)U_(F)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F3)~A_(L)U_(F3)~U_(M)U_(F)~C_(L4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(F)~C_(L4)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(F3)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(F3)~C_(L3)A_(F)~C_(M)C_(F3)~A_(M)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F12)~A_(L)U_(F12)~U_(M)U_(F)~C_(L4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(F)~C_(L4)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(F12)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(F12)~C_(L12)A_(F)~C_(M)C_(F12)~A_(M)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F18)~A_(L)U_(F18)~U_(M)U_(F)~C_(L4)A_(F)~C_(M)C_(F4)~A_(M)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(F)~C_(L4)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(F18)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(F18)~C_(L18)A_(F)~C_(M)C_(F18)~A_(M)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F3)~A_(L)U_(F3)~U_(M)U_(F)~C_(L4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(L)~A_(F)~U_(L3)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(F)~C_(L4)A_(F)~C_(M)C_(F)~A_(M)U~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(F3)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(F3)~C_(L3)A_(F)~C_(M)C_(F3)~A_(M)U~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F12)~A_(L)U_(F12)~U_(M)U_(F)~C_(L4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(L)~A_(F)~U_(L12)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(F)~C_(L4)A_(F)~C_(M)C_(F)~A_(M)U~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(F12)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(F12)~C_(L12)A_(F)~C_(M)C_(F12)~A_(M)U~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F18)~A_(L)U_(F18)~U_(M)U_(F)~C_(L4)A_(F)~C_(M)C_(F4)~A_(M)U~G_(L)~A_(F)~U_(L18)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(F)~C_(L4)A_(F)~C_(M)C_(F)~A_(M)U~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(F18)~C_(L)A_(F)~C_(M)C_(F)~A_(M)U~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(F18)~C_(L18)A_(F)~C_(M)C_(F18)~A_(M)U~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F)~A_(M)U_(L)~U_(M)U_(F)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F3)~A_(M)U_(L3)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(L)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L3)U_(F3)~A_(M)U_(L3)~U_(M3)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(M)U_(L3)~U_(M3)U_(F3)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(M)U_(L3)~U_(M3)U_(F3)~C_(M3)A_(F)~C_(M)C_(F3)~A_(L)U_(F)~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F12)~A_(M)U_(L12)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(L)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L12)U_(F12)~A_(M)U_(L12)~U_(M12)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(M)U_(L12)~U_(M12)U_(F12)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(M)U_(L12)~U_(M12)U_(F12)~C_(M12)A_(F)~C_(M)C_(F12)~A_(L)U_(F)~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F18)~A_(M)U_(L18)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(L)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L18)U_(F18)~A_(M)U_(L18)~U_(M18)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(M)U_(L18)~U_(M18)U_(F18)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(M)U_(L18)~U_(M18)U_(F18)~C_(M18)A_(F)~C_(M)C_(F18)~A_(L)U_(F)~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F3)~A_(M)U_(L3)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(L)U~G_(L)~A_(F)~U_(L3)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L3)U_(F3)~A_(M)U_(L3)~U_(M3)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(L)U~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(M)U_(L3)~U_(M3)U_(F3)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(L3)U_(F3)~A_(M)U_(L3)~U_(M3)U_(F3)~C_(M3)A_(F)~C_(M)C_(F3)~A_(L)U~G_(L)~A_(F)~U_(L3)~U_(F3)~U_(M3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F12)~A_(M)U_(L12)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(L)U~G_(L)~A_(F)~U_(L12)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L12)U_(F12)~A_(M)U_(L12)~U_(M12)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(L)U~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(M)U_(L12)~U_(M12)U_(F12)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(L12)U_(F12)~A_(M)U_(L12)~U_(M12)U_(F12)~C_(M12)A_(F)~C_(M)C_(F12)~A_(L)U~G_(L)~A_(F)~U_(L12)~U_(F12)~U_(M12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L)U_(F18)~A_(M)U_(L18)~U_(M)U_(F)~C_(M4)A_(F)~C_(M)C_(F4)~A_(L)U~G_(L)~A_(F)~U_(L18)~U_(F)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(L18)U_(F18)~A_(M)U_(L18)~U_(M18)U_(F)~C_(M4)A_(F)~C_(M)C_(F)~A_(L)U~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(M)U_(L18)~U_(M18)U_(F18)~C_(M)A_(F)~C_(M)C_(F)~A_(L)U~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(L18)U_(F18)~A_(M)U_(L18)~U_(M18)U_(F18)~C_(M18)A_(F)~C_(M)C_(F18)~A_(L)U~G_(L)~A_(F)~U_(L18)~U_(F18)~U_(M18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F)~A_(L)U_(F)~U_(M)U_(L)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F3)~A_(L)U_(F3)~U_(M)U_(L)~C_(M4)A_(F)~C_(M)C_(L4)~A_(M)U_(F)~G_(M)~A_(F)~U_(L3)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(L)~C_(M4)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L3)~U_(F3)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(L3)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L3)~U_(F3)~U_(L3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(L3)~C_(M3)A_(F)~C_(M)C_(L3)~A_(M)U_(F)~G_(M)~A_(F)~U_(L3)~U_(F3)~U_(L3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F12)~A_(L)U_(F12)~U_(M)U_(L)~C_(M4)A_(F)~C_(M)C_(L4)~A_(M)U_(F)~G_(M)~A_(F)~U_(L12)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(L)~C_(M4)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L12)~U_(F12)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(L12)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L12)~U_(F12)~U_(L12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(L12)~C_(M12)A_(F)~C_(M)C_(L12)~A_(M)U_(F)~G_(M)~A_(F)~U_(L12)~U_(F12)~U_(L12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F18)~A_(L)U_(F18)~U_(M)U_(L)~C_(M4)A_(F)~C_(M)C_(L4)~A_(M)U_(F)~G_(M)~A_(F)~U_(L18)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(L)~C_(M4)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L18)~U_(F18)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(L18)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U_(F)~G_(M)~A_(F)~U_(L18)~U_(F18)~U_(L18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(L18)~C_(M18)A_(F)~C_(M)C_(L18)~A_(M)U_(F)~G_(M)~A_(F)~U_(L18)~U_(F18)~U_(L18)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F3)~A_(L)U_(F3)~U_(M)U_(L)~C_(M4)A_(F)~C_(M)C_(L4)~A_(M)U~G_(M)~A_(F)~U_(L3)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(L)~C_(M4)A_(F)~C_(M)C_(L)~A_(M)U~G_(M)~A_(F)~U_(L3)~U_(F3)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(L3)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U~G_(M)~A_(F)~U_(L3)~U_(F3)~U_(L3)~A_(F)~G_(M)P-U_(M)~U_(F3)~U_(M3)U_(F3)~A_(L)U_(F3)~U_(M3)U_(L3)~C_(M3)A_(F)~C_(M)C_(L3)~A_(M)U~G_(M)~A_(F)~U_(L3)~U_(F3)~U_(L3)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F12)~A_(L)U_(F12)~U_(M)U_(L)~C_(M4)A_(F)~C_(M)C_(L4)~A_(M)U~G_(M)~A_(F)~U_(L12)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(L)~C_(M4)A_(F)~C_(M)C_(L)~A_(M)U~G_(M)~A_(F)~U_(L12)~U_(F12)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(L12)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U~G_(M)~A_(F)~U_(L12)~U_(F12)~U_(L12)~A_(F)~G_(M)P-U_(M)~U_(F12)~U_(M12)U_(F12)~A_(L)U_(F12)~U_(M12)U_(L12)~C_(M12)A_(F)~C_(M)C_(L12)~A_(M)U~G_(M)~A_(F)~U_(L12)~U_(F12)~U_(L12)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M)U_(F18)~A_(L)U_(F18)~U_(M)U_(L)~C_(M4)A_(F)~C_(M)C_(L4)~A_(M)U~G_(M)~A_(F)~U_(L18)~U_(F)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F)~U_(M18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(L)~C_(M4)A_(F)~C_(M)C_(L)~A_(M)U~G_(M)~A_(F)~U_(L18)~U_(F18)~U_(L)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(L18)~C_(M)A_(F)~C_(M)C_(L)~A_(M)U~G_(M)~A_(F)~U_(L18)~U_(F18)~U_(L18)~A_(F)~G_(M)P-U_(M)~U_(F18)~U_(M18)U_(F18)~A_(L)U_(F18)~U_(M18)U_(L18)~C_(M18)A_(F)~C_(M)C_(L18)~A_(M)U~G_(M)~A_(F)~U_(L18)~U_(F18)~U_(L18)~A_(F)~G_(M)

Table 15 Examples of Murine Apo-B ags-siRNA Compounds A. Murine Apo-BAgs-RNAi Compositions Described in the Art:

UUGAUCUAAAUGCAUUGUG

Haringsma et al. (Nucleic Acids Res 40: 4125-36, 2012) used thissequence to generate ssRNAi compounds against murine APO-B target site6981 including the following:

P-U_(F)U_(F)G_(F)A_(F)U_(F)C_(F)U_(F)A_(F)A_(F)A_(F)U_(F)G_(F)C_(F)A_(F)U_(F)U_(F)G_(F)U_(F)G_(F)U_(M)U_(M)

Any of the 5′-end nucleosides (P-U_(F) or P-U_(M)) shown in the examplesof agsRNAi compounds in Tables 15A and 15B can be replaced with any ofthose provided for herein including one of the 5′end nucleosidesselected from the group consisting of: P-G_(F), P-G_(M), P-G_(N),P-G_(L), P-G_(Z), P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T),P-G_(W), P-G_(V), P-G_(O), P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z),P-C_(H), P-C_(B), P-C_(K), P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V),P-C_(O), P-U_(F), P-U_(M), P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K),P-U_(Q), P-U_(S), P-U_(T), P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H),5′-VP-U_(Z), 5′-VP-U_(K), 5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe),5′-VP-T_(E), 5′-VP-U_(E), 5′-VP-T_(Z), 5′-VP-Q_(E), 5′-VP-T_(Q) and5′-VP-T_(B).

Any of the nucleosides in Tables 15A and 15B with an L modification(s)found in one or more positions 2-19 can have any given L or set of Lsreplaced with any of those sugar, sugar analogs or sugar substitutesprovided for herein for positions 2-19 including one or more of thoseindependently selected from the group consisting of: S, J, W, V, Q, Y,O, T and cet (i.e., if multiple Ls are replaced the selectedreplacements do not all have to be the same sugar, sugar analog or sugarsubstitute).

Any of the compounds in Tables 15A and 15B can any of those units andlinkages provided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

TABLE 15A Compositions of Matter Suitable for Use in vitro or in aSubject with a Protective Carrier 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TABLE 15B Compositions of Matter Suitable for Administration to aSubject with or without a Protective Carrier and for Any Other use asProvided for Herein (5′-3′)P-U_(M)~U_(F3)~G_(M)A_(F)~U_(M3)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A_(F)~U_(M3)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M3)C_(F)~U_(M3)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A_(F)~U_(M3)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M3)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M3)G_(F)~C_(M)A_(F)~U_(M3)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M3)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A_(F)~U_(M3)~U_(F3)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A_(F)~U_(M)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(F)~U_(M3)C_(F4)~U_(M3)A_(F)~A_(M)A_(F)~U_(M3)G_(F)~C_(M4)A_(F)~U_(M3)~U_(F3)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M12)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A_(F)~U_(M12)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M12)C_(F)~U_(M12)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A_(F)~U_(M12)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M12)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M12)G_(F)~C_(M)A_(F)~U_(M12)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M12)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A_(F)~U_(M12)~U_(F12)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A_(F)~U_(M)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M12)C_(F4)~U_(M12)A_(F)~A_(M)A_(F)~U_(M12)G_(F)~C_(M4)A_(F)~U_(M12)~U_(F12)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(F)~U_(M18)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A_(F)~U_(M18)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M18)C_(F)~U_(M18)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A_(F)~U_(M18)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M18)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M18)G_(F)~C_(M)A_(F)~U_(M18)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M18)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A_(F)~U_(M18)~U_(F18)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A_(F)~U_(M)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(F)~U_(M18)C_(F4)~U_(M18)A_(F)~A_(M)A_(F)~U_(M18)G_(F)~C_(M4)A_(F)~U_(M18)~U_(F18)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(F)~U_(M3)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A~U_(M3)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M3)C_(F)~U_(M3)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A~U_(M3)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M3)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M3)G_(F)~C_(M)A~U_(M3)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M3)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A~U_(M3)~U_(F3)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A~U_(M)~U_(F)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(F)~U_(M3)C_(F4)~U_(M3)A_(F)~A_(M)A_(F)~U_(M3)G_(F)~C_(M4)A~U_(M3)~U_(F3)~G_(M)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M12)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A~U_(M12)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M12)C_(F)~U_(M12)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A~U_(M12)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M12)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M12)G_(F)~C_(M)A~U_(M12)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M12)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A~U_(M12)~U_(F12)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A~U_(M)~U_(F)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M12)C_(F4)~U_(M12)A_(F)~A_(M)A_(F)~U_(M12)G_(F)~C_(M4)A~U_(M12)~U_(F12)~G_(M)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(F)~U_(M18)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A~U_(M18)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M18)C_(F)~U_(M18)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A~U_(M18)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M18)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M18)G_(F)~C_(M)A~U_(M18)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(F)~U_(M18)C_(F)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M)A~U_(M18)~U_(F18)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(F)~A_(M)A_(F)~U_(M)G_(F)~C_(M4)A~U_(M)~U_(F)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(F)~U_(M18)C_(F4)~U_(M18)A_(F)~A_(M)A_(F)~U_(M18)G_(F)~C_(M4)A~U_(M18)~U_(F18)~G_(M)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(L)A_(F)~U_(M)C_(L)~U_(M)A_(F)~A_(L)A_(F)~U_(M)~G_(L)~C_(M)~A_(F)~U_(L)~U_(F)~G_(L)~U_(F)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(L)A_(F)~U_(M)C_(L)~U_(M)A_(F)~A_(L)A_(F)~U_(M)~G_(L)~C_(M)A~U_(L)~U_(F)~G_(L)~U_(F)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(L)A_(F)~U_(M3)C_(L4)~U_(M)A_(F)~A_(L)A_(F)~U_(M)G_(L)~C_(M4)A_(F)~U_(L3)~U_(F)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(L)A_(F)~U_(M3)C_(L)~U_(M3)A_(F)~A_(L)A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~U_(L)~U_(F)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(L)~U_(M3)C_(F4)~U_(M3)A_(L)~A_(M)A_(L)~U_(M3)G_(L)~C_(M4)A_(F)~U_(L3)~U_(F3)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(L)~U_(M12)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A_(F)~U_(L12)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M12)C_(F)~U_(M12)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A_(F)~U_(L12)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M12)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M12)G_(L)~C_(M)A_(F)~U_(L12)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M12)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A_(F)~U_(L12)~U_(F12)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(F)~U_(M)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A_(F)~U_(L)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(L)~U_(M12)C_(F4)~U_(M12)A_(L)~A_(M)A_(L)~U_(M12)G_(L)~C_(M4)A_(F)~U_(L12)~U_(F12)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(L)~U_(M18)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A_(F)~U_(L18)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M18)C_(F)~U_(M18)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A_(F)~U_(L18)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M18)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M18)G_(L)~C_(M)A_(F)~U_(L18)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M18)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A_(F)~U_(L18)~U_(F18)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(L)~U_(M)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A_(F)~U_(L)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(L)~U_(M18)C_(F4)~U_(M18)A_(L)~A_(M)A_(L)~U_(M18)G_(L)~C_(M4)A_(F)~U_(L18)~U_(F18)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(L)~U_(M3)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A~U_(L3)~U_(F)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M3)C_(F)~U_(M3)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A~U_(L3)~U_(F)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M3)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M3)G_(L)~C_(M)A~U_(L3)~U_(F)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M3)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A~U_(L3)~U_(F3)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(L)~U_(M)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A~U_(L)~U_(F)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F3)~G_(M)A_(L)~U_(M3)C_(F4)~U_(M3)A_(L)~A_(M)A_(L)~U_(M3)G_(L)~C_(M4)A~U_(L3)~U_(F3)~G_(L)~U_(F3)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(L)~U_(M12)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A~U_(L12)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M12)C_(F)~U_(M12)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A~U_(L12)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M12)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M12)G_(L)~C_(M)A~U_(L12)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M12)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A~U_(L12)~U_(F12)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(L)~U_(M)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A~U_(L)~U_(F)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F12)~G_(M)A_(L)~U_(M12)C_(F4)~U_(M12)A_(L)~A_(M)A_(L)~U_(M12)G_(L)~C_(M4)A~U_(L12)~U_(F12)~G_(L)~U_(F12)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(L)~U_(M18)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A~U_(L18)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M18)C_(F)~U_(M18)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A~U_(L18)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M18)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M18)G_(L)~C_(M)A~U_(L18)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F)~G_(M)A_(L)~U_(M18)C_(F)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M)A~U_(L18)~U_(F18)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(L)~U_(M)C_(F4)~U_(M)A_(L)~A_(M)A_(L)~U_(M)G_(L)~C_(M4)A~U_(L)~U_(F)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)P-U_(M)~U_(F18)~G_(M)A_(L)~U_(M18)C_(F4)~U_(M18)A_(L)~A_(M)A_(L)~U_(M18)G_(L)~C_(M4)A~U_(L18)~U_(F18)~G_(L)~U_(F18)~G_(M)~A_(F)~G_(M)

Table 16 Examples of Murine Apo-B ags-siRNA Compounds

UUAAG_(F)GAAGCCUUACUGG

Haringsma et al. (Nucleic Acids Res 40: 4125-36, 2012) used thissequence to generate ssRNAi compounds against murine APO-B target site8786 including the following:

P-U_(F)U_(F)A_(F)A_(F)G_(F)A_(F)G_(F)A_(F)A_(F)G_(F)C_(F)C_(F)U_(F)U_(F)A_(F)C_(F)U_(F)G_(F)G_(F)U_(M)U_(M)

Any of the 5′-end nucleosides (P-U_(F) or P-U_(M)) shown in the examplesof agsRNAi compounds in Tables 16A and 16B can be replaced with any ofthose provided for herein including one of the 5′end nucleosidesselected from the group consisting of: P-G_(F), P-G_(M), P-G_(N),P-G_(L), P-G_(Z), P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T),P-G_(W), P-G_(V), P-G_(O), P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(H),P-C_(B), P-C_(K), P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O),P-U_(F), P-U_(M), P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q),P-U_(S), P-U_(T), P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H),5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Tables 16A and 16B with an L modification(s)found in one or more positions 2-19 can have any given L or set of Lsreplaced with any of those sugar, sugar analogs or sugar substitutesprovided for herein for positions 2-19 including one or more of thoseindependently selected from the group consisting of: S, J, W, V, Q, Y,O, T and cet (i.e., if multiple Ls are replaced the selectedreplacements do not all have to be the same sugar, sugar analog or sugarsubstitute).

Any of the nucleosides in Tables 16A and 16B with an L modificationfound in the overhang precursor can have the L replaced with any ofthose units and linkages provided for herein for overhang precursorsincluding one or more of the sugar or sugar analogs independentlyselected from the group consisting of: F, J, W, V, Y, T, TL and I.

Any of the compounds in Tables 16A and 16B can any of those units andlinkages provided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

TABLE 16A Compositions of Matter Suitable for Use in vitro or in aSubject with a Protective Carrier 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TABLE 16B Compositions of Matter Suitable for Administration to aSubject with or without a Protective Carrier and for Any Other use asProvided for Herein (5′-3′)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F)~U_(M3)U_(F)~A_(M)C_(F)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M3)U_(F)~A_(M)C_(F)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M3)U_(F)~A_(M)C_(F4)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M4)C_(F4)~U_(M3)U_(F)~A_(M)C_(F4)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F)~U_(M12)U_(F)~A_(M)C_(F)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M12)U_(F)~A_(M)C_(F)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M12)U_(F)~A_(M)C_(F4)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M4)C_(F4)~U_(M12)U_(F)~A_(M)C_(F4)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F)~U_(M18)U_(F)~A_(M)C_(F)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M18)U_(F)~A_(M)C_(F)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M18)U_(F)~A_(M)C_(F4)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M4)C_(F4)~U_(M18)U_(F)~A_(M)C_(F4)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F)~U_(M3)U~A_(M)C_(F)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M3)U~A_(M)C_(F)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M3)U~A_(M)C_(F4)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M4)C_(F4)~U_(M3)U~A_(M)C_(F4)~U_(M3)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F)~U_(M12)U~A_(M)C_(F)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M12)U~A_(M)C_(F)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M12)U~A_(M)C_(F4)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M4)C_(F4)~U_(M12)U~A_(M)C_(F4)~U_(M12)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F)~U_(M18)U~A_(M)C_(F)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M18)U~A_(M)C_(F)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M)C_(F4)~U_(M18)U~A_(M)C_(F4)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(F)~G_(M)A_(F)~G_(M)A_(F)~A_(M)G_(F)~C_(M4)C_(F4)~U_(M18)U~A_(M)C_(F4)~U_(M18)~G_(F)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F)~U_(M)U_(F)~A_(L)C_(F)~U_(M)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F)~U_(M)U~A_(L)C_(F)~U_(M)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F)~U_(M3)U_(F)~A_(L)C_(F)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F4)~U_(M3)U_(F)~A_(L)C_(F)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F4)~U_(M3)U_(F)~A_(L)C_(F4)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M4)C_(F4)~U_(M3)U_(F)~A_(L)C_(F4)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F)~U_(M12)U_(F)~A_(L)C_(F)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F4)~U_(M12)U_(F)~A_(L)C_(F)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F4)~U_(M12)U_(F)~A_(L)C_(F4)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M4)C_(F4)~U_(M12)U_(F)~A_(L)C_(F4)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F)~U_(M18)U_(F)~A_(L)C_(F)~U_(M)18~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F4)~U_(M18)U_(F)~A_(L)C_(F)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M)C_(F4)~U_(M18)U_(F)~A_(L)C_(F4)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(L)A_(F)~G_(M)A_(L)~G_(M)A_(F)~A_(L)G_(F)~C_(M4)C_(F4)~U_(M18)U_(F)~A_(L)C_(F4)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(L)A_(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(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M4)C_(F4)~U_(L18)U_(F)~A_(L)C_(F4)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F)~U_(L3)U~A_(L)C_(F)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F4)~U_(L3)U~A_(L)C_(F)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F4)~U_(L3)U~A_(L)C_(F4)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F3)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M4)C_(F4)~U_(L3)U~A_(L)C_(F4)~U_(M3)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F)~U_(L12)U~A_(L)C_(F)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F4)~U_(L12)U~A_(L)C_(F)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F4)~U_(L12)U~A_(L)C_(F4)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F12)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M4)C_(F4)~U_(L12)U~A_(L)C_(F4)~U_(M12)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F)~U_(L18)U~A_(L)C_(F)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F4)~U_(L18)U~A_(L)C_(F)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M)C_(F4)~U_(L18)U~A_(L)C_(F4)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)P-U_(M)~U_(F18)~A_(M)A_(L)~G_(M)A_(L)~G_(M)A_(L)~A_(M)G_(F)~C_(M4)C_(F4)~U_(L18)U~A_(L)C_(F4)~U_(M18)~G_(L)~G_(M)~A_(L)~A_(L)~G_(F)

Table 17 Examples of Murine Apo-B ags-siRNA Compounds

AUUUCAGGAAUUGUUAAAG

Haringsma et al. (Nucleic Acids Res 40: 4125-36, 2012) used thissequence to generate ssRNAi compounds against murine APO-B target site9470 including the following:

P-A_(F)U_(F)U_(F)U_(F)C_(F)A_(F)G_(F)G_(F)A_(F)A_(F)U_(F)U_(F)G_(F)U_(F)U_(F)A_(F)A_(F)A_(F)G_(F)U_(M)U_(M)

Any of the 5′-end nucleosides (P-A_(F)) shown in the examples of agsRNAicompounds in Table 17 can be replaced with any of those provided forherein including one of the 5′end nucleosides selected from the groupconsisting of: P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z), P-C_(H), P-C_(B), P-C_(K),P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O), P-U_(F), P-U_(M),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 17 with an L modification(s) found inone or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the nucleosides in Table 17 with an L modification found in theoverhang precursor can have the L replaced with any of those units andlinkages provided for herein for overhang precursors including one ormore of the sugar or sugar analogs independently selected from the groupconsisting of: F, J, W, V, Y, T, TL and I.

Any of the nucleosides in Table 17 can have any of those units andlinkages provided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

Compositions of Matter Suitable for Use in vitro or in a Subject with aProtective Carrier 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Table 18 Application of AGSD to Murine Apo-B ags-siRNA

UUGGUAUUCAGUGUGAUGA

Haringsma et al. (Nucleic Acids Res 40: 4125-36, 2012) used thissequence to generate ssRNAi compounds against murine APO-B target site10127 including the following:

P-U_(F)U_(F)G_(F)G_(F)U_(F)A_(F)U_(F)U_(F)C_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F)A_(F)U_(F)G_(F)A_(F)U_(M)U_(M)

Any of the 5′-end nucleosides (P-U_(F)) shown in the examples of agsRNAicompounds in Table 18 can be replaced with any of those provided forherein including one of the 5′end nucleosides selected from the groupconsisting of: P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z), P-C_(H), P-C_(B), P-C_(K),P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O), P-U_(F), P-U_(M),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 18 with an L modification(s) found inone or more positions 2-19 can have any given L or set of Ls replacedwith any of those sugar, sugar analogs or sugar substitutes provided forherein for positions 2-19 including one or more of those independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the nucleosides in Table 18 with an L modification found in theoverhang precursor can have the L replaced with any of those units andlinkages provided for herein for overhang precursors including one ormore of the sugar or sugar analogs independently selected from the groupconsisting of: F, J, W, V, Y, T, TL and I.

Any of the nucleosides in Table 18 can have any of those units andlinkages provided for herein for overhang precursors.

B. Examples of Application of AGSD to this Compound:

Compositions of Matter Suitable for Use in vitro or in a Subject with aProtective Carrier (5′-3′)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F)U_(F)C_(F4)A_(F)G_(F)U_(F3)G_(F)U_(F)G_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F3)U_(F3)C_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F3)U_(F3)C_(F)A_(F)G_(F)U_(F3)G_(F)U_(F)G_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F3)U_(F3)C_(F4)A_(F)G_(F)U_(F3)G_(F)U_(F3)G_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F)U_(F)C_(F4)A_(F)G_(F)U_(F12)G_(F)U_(F)G_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F12)U_(F12)C_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F12)U_(F12)C_(F)A_(F)G_(F)U_(F12)G_(F)U_(F)G_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F12)U_(F12)C_(F4)A_(F)G_(F)U_(F12)G_(F)U_(F12)G_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F)U_(F)C_(F4)A_(F)G_(F)U_(F18)G_(F)U_(F)G_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F18)U_(F18)C_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F18)U_(F18)C_(F)A_(F)G_(F)U_(F18)G_(F)U_(F)G_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F18)U_(F18)C_(F4)A_(F)G_(F)U_(F18)G_(F)U_(F18)G_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F)U_(F)C_(F4)A_(F)G_(F)U_(F3)G_(F)UG_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F3)U_(F3)C_(F)A_(F)G_(F)U_(F)G_(F)UG_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F3)U_(F3)C_(F)A_(F)G_(F)U_(F3)G_(F)UG_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(F)U_(F3)A_(F)U_(F3)U_(F3)C_(F4)A_(F)G_(F)U_(F3)G_(F)U₃G_(F)A_(F)U_(F3)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F)U_(F)C_(F4)A_(F)G_(F)U_(F12)G_(F)UG_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F12)U_(F12)C_(F)A_(F)G_(F)U_(F)G_(F)UG_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F12)U_(F12)C_(F)A_(F)G_(F)U_(F12)G_(F)UG_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(F)U_(F12)A_(F)U_(F12)U_(F12)C_(F4)A_(F)G_(F)U_(F12)G_(F)U₁₂G_(F)A_(F)U_(F12)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F)U_(F)C_(F4)A_(F)G_(F)U_(F18)G_(F)UG_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F18)U_(F18)C_(F)A_(F)G_(F)U_(F)G_(F)UG_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F18)U_(F18)C_(F)A_(F)G_(F)U_(F18)G_(F)UG_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(F)U_(F18)A_(F)U_(F18)U_(F18)C_(F4)A_(F)G_(F)U_(F18)G_(F)U₁₈G_(F)A_(F)U_(F18)G_(F)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F)G_(F)G_(L)U_(F)A_(F)U_(F)U_(F)C_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(L)A_(F)U_(F)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F)G_(F)G_(L)U_(F)A_(F)U_(F)U_(F)C_(L)A_(F)G_(F)U_(L)G_(F)UG_(L)A_(F)U_(F)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F)U_(F)C_(L4)A_(F)G_(F)U_(L3)G_(F)U_(F)G_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F3)U_(F3)C_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F3)U_(F3)C_(L)A_(F)G_(F)U_(L3)G_(F)U_(F)G_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F3)U_(F3)C_(L4)A_(F)G_(F)U_(L3)G_(F)U_(F3)G_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(L)U_(F12)A_(F)U_(F)U_(F)C_(L4)A_(F)G_(F)U_(L12)G_(F)U_(F)G_(L)A_(F)U_(F12)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(L)U_(F12)A_(F)U_(F12)U_(F12)C_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(L)A_(F)U_(F12)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(L)U_(F12)A_(F)U_(F12)U_(F12)C_(L)A_(F)G_(F)U_(L12)G_(F)U_(F)G_(L)A_(F)U_(F12)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F12)G_(F)G_(L)U_(F12)A_(F)U_(F12)U_(F12)C_(L4)A_(F)G_(F)U_(L12)G_(F)U_(F12)G_(L)A_(F)U_(F12)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(L)U_(F18)A_(F)U_(F)U_(F)C_(L4)A_(F)G_(F)U_(L18)G_(F)U_(F)G_(L)A_(F)U_(F18)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(L)U_(F18)A_(F)U_(F18)U_(F18)C_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(L)A_(F)U_(F18)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(L)U_(F18)A_(F)U_(F18)U_(F18)C_(L)A_(F)G_(F)U_(L18)G_(F)U_(F)G_(L)A_(F)U_(F18)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(F)G_(L)U_(F18)A_(F)U_(F18)U_(F18)C_(L4)A_(F)G_(F)U_(L18)G_(F)U_(F18)G_(L)A_(F)U_(F18)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F)U_(F)C_(L4)A_(F)G_(F)U_(L3)G_(F)UG_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F3)U_(F3)C_(L)A_(F)G_(F)U_(L)G_(F)UG_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F3)U_(F3)C_(L)A_(F)G_(F)U_(L3)G_(F)UG_(L)A_(F)U_(F3)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F3)G_(F)G_(L)U_(F3)A_(F)U_(F3)U_(F3)C_(L4)A_(F)G_(F)U_(L3)G_(F)U₃G_(L)A_(F)U_(F3)G_(L)A_(F)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)P-U_(F)U_(F18)G_(L)G_(F)U_(F18)A_(L)U_(F18)U_(L18)C_(F)A_(F)G_(F)U_(L18)G_(F)UG_(F)A_(L)U_(F18)G_(L)A_(F)A_(L)G_(L)G_(F)P-U_(F)U_(F18)G_(L)G_(F)U_(F18)A_(L)U_(F18)U_(L18)C_(F4)A_(F)G_(F)U_(L18)G_(F)U₁₈G_(F)A_(L)U_(F18)G_(L)A_(F)A_(L)G_(L)G_(F)

Table 19 Examples of Seven Seed Vehicles Suitable for Use with a 5′-EndModule Consisting of the Nine 5′-End Nucleosides of any MiRNA GuideStand A. Seed Vehicles Designed and Evaluated by Chorn et al., RNA 18:1796-804, 2012.

AGSD can be applied to any ss-RNAi known in the art to improve itsactivity, potency and/or duration of effect. In the case of ags-MiRsthat use their seed sequence to find their targets, however, the modularapproach can be used as an alternative to modifying the endogenous miRNAguide strand to be mimicked.

The modular approach involves the use of a 5′-end module that is an8-mer or 9-mer that includes the seed sequence of the miRNA guide strandto be mimicked (or a novel seed sequence) along with a seed vehicle andtypically an overhang precursor. Seed vehicles are 11 or 10-mersdepending on the length of the 5′-end module to produce a 19-merexclusive of any overhang precursor. A seed vehicle can have any RNAsequence comprising the standard bases (A, U, G and C), but in order todemonstrate the advantages of ags-MiRs over the best ss-RNAi miRNAmimics known in the art the examples found in Tables 20 and 21 make useof the best of the known seed vehicle sequences after they haveundergone AGSD modifications.

The best seed vehicles come from Chorn et al. (RNA 18: 1796-804, 2012).They evaluated 88 miRNA-124 mimics constructed using the modularapproach. The 5′-end module (positions 1-9) (UAAGGCACG) contained themiR-124 seed sequence and the seed vehicles (positions 10-19) hadrandomly selected sequences. All the linkages in these compounds werephosphodiester and all the nucleosides had the 2′-fluoro modification innucleoside positions 1-19. In addition all of the compounds had aU_(M)U_(M) overhang precursor.

These 88 compounds were tested for activity following transfection ofHCT-116 cells grown in culture. Of these 88 compounds 7 (7y_4, 8y_3,8y_4, 9y_2, 9y_3, 10y_1 and 10y_7) had the highest levels of activity.Their activity levels, however, were not statistically significantlydifferent. These seed vehicles are shown in Table 19A and are designatedby the name of the Chorn et al. compound in which they are found.

TABLE 19A Seed Vehicles Used by Chorn et al. (2012) that Provided theHighest ss-RNAi miRNA Mimic Activity Seed Vehicle Designation ModifiedSeed Vehicle Sequence 7y_4G_(F)U_(F)C_(F)U_(F)U_(F)A_(F)U_(F)U_(F)U_(F)G_(F) 8y_3U_(F)G_(F)C_(F)U_(F)C_(F)C_(F)C_(F)A_(F)C_(F)C_(F) 8y_4C_(F)C_(F)C_(F)U_(F)C_(F)C_(F)C_(F)U_(F)G_(F)A_(F) 9y_2C_(F)G_(F)C_(F)U_(F)U_(F)C_(F)U_(F)C_(F)U_(F)U_(F) 9y_3U_(F)U_(F)C_(F)U_(F)C_(F)G_(F)U_(F)C_(F)U_(F)C_(F) 10y_1U_(F)C_(F)C_(F)C_(F)U_(F)U_(F)C_(F)U_(F)U_(F)C_(F) 10y_7C_(F)U_(F)C_(F)C_(F)C_(F)U_(F)U_(F)U_(F)C_(F)U_(F)B. Application of AGSD to these Modular Components and Compounds:

Tables 19B and 19C provide examples of the seed vehicles shown in Table19A that have been modified by AGSD. Table 19B uses the same level ofbasic nuclease resistance for the seed sequence as was used by Chorn etal. which requires any ags-MIR based on them to be used with aprotective carrier when treating subjects. The examples in Table 19Bhave a higher level of basic nuclease resistance suitable for use inags-MiRs to be used with or without a protective carrier when treatingsubjects.

Any of the nucleosides in Tables 19B or 19C with an L modification foundin one or more nucleoside positions 10-19 can have any given L or set ofLs replaced with any of those sugar, sugar analogs or sugar substitutesprovided for herein for positions 2-19 including one or more of thoseindependently selected from the group consisting of S, J, W, V, Q, Y, O,T and cet (i.e., if multiple Ls are replaced the selected replacementsdo not all have to be the same sugar, sugar analog or sugar substitute).

Any of the examples of seed vehicles shown in Table 19B or 19C can haveany of the overhang precursors provided for herein.

TABLE 19B Examples of the Application of AGSD to the Seed Vehicles usedby Chorn et al. (2012) Compositions of Matter Suitable Seed Vehicle forUse in vitro or in a Subject with Designation a Protective Carrier(5′-3′) 7y_4 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TABLE 19C Examples of the Application of AGSD to the Seed Vehicles usedby Chorn et al. (2012) with a Higher Level of Basic Nuclease ProtectionSeed Compositions of Matter Suitable for Use Vehicle in vitro or in aSubject with or Designation without a Protective Carrier (5′-3′) 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Table 20 Examples of Murine/Human miR-124 ags-MiR Compositions Based onModular Design A. Endogenous Guide Strand Sequence;

The murine/human miR-124 guide strand sequence based on miRBaseaccession numbers MI0000150 and MI0000443 minus the overhang is asfollows:

UAAGGCACGCGGUGAAUGCB. Select Murine/Human MiR-124 ss-RNAi Compositions Designed andEvaluated by Chorn et al., RNA 18: 1796-804, 2012.

The following two ss-RNAi mimics of miR-124 are examples of thoseevaluated by Chorn et al.

The first example is based on the endogenous guide strand where theendogenous overhang is replaced by U_(M)U_(M):

P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(F)C_(F)G_(F)C_(F)G_(F)G_(F)U_(F)G_(F)A_(F)A_(F)U_(F)G_(F)C_(F)C_(F)U_(M)U_(M)

The second example is based on the modular approach and it incorporatesseed vehicle 9y_2 that is shown in Table 19A:

P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(F)C_(F)G_(F)C_(F)G_(F)C_(F)U_(F)U_(F)C_(F)U_(F)C_(F)U_(F)U_(F)U_(M)U_(M)C. Application of AGSD to these Modular Components and Compounds:

As for any ss-RNAi the endogenous miR-124 sequence can be modified forbasic nuclease resistance and by AGSD. Further it can have any of theoverhang precursors provided herein.

The nine-nucleoside long 5′-end module containing the miR-124 sequenceused by Chorn et al. (2012) isP-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(F)C_(F). Examples of this 5′-endmodule as modified by AGSD are provided in Table 20A while examples witha higher level of basic nuclease resistance than used by Chorn et al.are provided in Table 20B.

Any of the 5′-end nucleosides (P-U_(M)) shown in the examples of agsRNAicompounds in

Table 20A and 20B can be replaced with any of those provided for hereinincluding where one of the 5′end nucleosides is selected from the groupconsisting of P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z), P-G_(H),P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(V), P-G_(O),P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z), P-C_(H), P-C_(B), P-C_(K),P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O), P-U_(F), P-U_(M),P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S), P-U_(T),P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z), 5′-VP-U_(K),5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E), 5′-VP-U_(E),5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 20A or 20B with an L modification(s)found in one or more of those in positions 2-9 can have any given L orset of Ls replaced with any of those sugar or sugar analogs provided forherein for positions 2-19 including one or more of them independentlyselected from the group consisting of: S, J, W, V, Q, Y, O, T and cet(i.e., if multiple Ls are replaced the selected replacements do not allhave to be the same sugar, sugar analog or sugar substitute).

Any of the 5′-end modules shown in Table 20A can be used with any seedvehicle shown in Table 19B while any of the 5′-end modules shown inTable 20B can be used with any seed vehicle shown in Table 19C. Further,any of the resulting compounds can have any of the overhang precursorsprovided for herein.

TABLE 20A Examples of the Application of AGSD to the 5′-end Module formiR-124 used by Chorn et al. (2012) Compositions of Matter Suitable forUse in vitro or in a Subject with a Protective Carrier (5′-3′)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(F)C_(F)G_(L)P-U_(F)A_(F)A_(L)G_(F)G_(L)C_(F)A_(F)C_(F)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F4)A_(F)C_(F4)G_(F)P-U_(F)A_(F)A_(L)G_(F)G_(L)C_(F)A_(L)C_(F)G_(F)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(F)C_(F)G_(L)P-U_(F)A_(F)A_(L)G_(F)G_(L)C_(F)A_(L)C_(F)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F4)A_(F)C_(F4)G_(L)P-U_(F)A_(F)A_(F)G_(L)G_(F)C_(L)A_(F)C_(L)G_(F)P-U_(F)A_(L)A_(F)G_(F)G_(F)C_(F)A_(F)C_(F)G_(F)P-U_(F)A_(L)A_(F)G_(L)G_(F)C_(L)A_(F)C_(L)G_(F)P-U_(F)A_(F)A_(L)G_(F)G_(F)C_(F)A_(F)C_(F)G_(F)P-U_(F)A_(F)A_(F)G_(L)G_(F)C_(F)A_(F)C_(L)G_(F)P-U_(F)A_(F)A_(F)G_(L)G_(F)C_(F)A_(F)C_(F)G_(F)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(L4)A_(F)C_(L4)G_(F)P-U_(F)A_(F)A_(F)G_(F)G_(L)C_(F)A_(F)C_(F)G_(F)P-U_(F)A_(F)A_(L)G_(F)G_(F)C_(L4)A_(F)C_(L4)G_(F)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(L)C_(F)G_(F)P-U_(F)A_(L)A_(F)G_(L)G_(F)C_(L4)A_(F)C_(L4)G_(F)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(L)A_(F)C_(F)G_(F)P-U_(F)A_(F)A_(F)G_(L)G_(F)C_(F)A_(F)C_(F4)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(F)C_(L)G_(F)P-U_(F)A_(F)A_(L)G_(F)G_(L)C_(F)A_(F)C_(F4)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(L)C_(F)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F4)A_(L)C_(F)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F)A_(L)C_(F4)G_(L)P-U_(F)A_(F)A_(F)G_(F)G_(F)C_(F4)A_(L)C_(F4)G_(L)

TABLE 20B Examples of the Application of AGSD to the 5′-end Module ormiR-124 used by Chorn et al. (2012) as Adjusted for Use in Subjects withor without a Protective Carrier Compositions of Matter Suitable forAdministration to a Subject with or without a Protective Carrier and forAny Other use as Provided for Herein (5′-3′)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F)~A_(M)C_(F)~G_(L)P-U_(M)~A_(F)~A_(L)G_(F)~G_(L)C_(F)~A_(M)C_(F)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F4)~A_(M)C_(F4)~G_(M)P-U_(M)~A_(F)~A_(L)G_(F)~G_(L)C_(F)~A_(L)C_(F)~G_(M)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F4)~A_(M)C_(F)~G_(L)P-U_(M)~A_(F)~A_(L)G_(F)~G_(L)C_(F)~A_(L)C_(F)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F4)~A_(M)C_(F4)~G_(L)P-U_(M)~A_(F)~A_(M)G_(L)~G_(M)C_(L)~A_(M)C_(L)~G_(M)P-U_(M)~A_(L)~A_(M)G_(F)~G_(M)C_(F)~A_(M)C_(F)~G_(M)P-U_(M)~A_(L)~A_(M)G_(L)~G_(M)C_(L)~A_(M)C_(L)~G_(M)P-U_(M)~A_(F)~A_(L)G_(F)~G_(M)C_(F)~A_(M)C_(F)~G_(M)P-U_(M)~A_(F)~A_(M)G_(L)~G_(M)C_(F)~A_(M)C_(L)~G_(M)P-U_(M)~A_(F)~A_(M)G_(L)~G_(M)C_(F)~A_(M)C_(F)~G_(M)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(L4)~A_(M)C_(L4)~G_(M)P-U_(M)~A_(F)~A_(M)G_(F)~G_(L)C_(F)~A_(M)C_(F)~G_(M)P-U_(M)~A_(F)~A_(L)G_(F)~G_(M)C_(L4)~A_(M)C_(L4)~G_(M)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F)~A_(L)C_(F)~G_(M)P-U_(M)~A_(L)~A_(M)G_(L)~G_(M)C_(L4)~A_(M)C_(L4)~G_(M)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(L)~A_(M)C_(F)~G_(M)P-U_(M)~A_(F)~A_(M)G_(L)~G_(M)C_(F)~A_(M)C_(F4)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F)~A_(M)C_(L)~G_(M)P-U_(M)~A_(F)~A_(L)G_(F)~G_(L)C_(F)~A_(M)C_(F4)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F)~A_(L)C_(F)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F4)~A_(L)C_(F)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F)~A_(L)C_(F4)~G_(L)P-U_(M)~A_(F)~A_(M)G_(F)~G_(M)C_(F4)~A_(L)C_(F4)~G_(L)

Table 21 Murine/Human MiR-122 ags-MiR Compositions Based on theEndogenous Sequence or on Modular Design A. Endogenous Guide StrandSequence;

The murine/human miR-122 guide strand based on miRBase accession numbersMI0000256 and MI0000442 minus the overhang is as follows:

UGGAGUGUGACAAUGGUGUB. Select Murine/Human MiR-122 ss-RNAi Compositions Designed andEvaluated by Chorn et al., RNA 18: 1796-804, 2012.

The following two ss-RNAi mimics of miR-122 are examples of thoseevaluated by Chorn et al.

The first example is based on the endogenous guide strand where theendogenous overhang is replaced by U_(M)U_(M):

Modified Endogenous miR-122 Compound:

P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F)A_(F)C_(F)A_(F)A_(F)U_(F)G_(F)G_(F)U_(F)G_(F)U_(F)U_(M)U_(M)

The second example is based on the modular approach and it incorporatesseed vehicle 9y_2 that is shown in Table 19A:

P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F)C_(F)G_(F)C_(F)U_(F)U_(F)C_(F)U_(F)C_(F)U_(F)U_(F)U_(M)U_(M)C. Application of AGSD to these Modular Components and Compounds:

As for any ss-RNAi the endogenous miR-122 sequence can be modified forbasic nuclease resistance and by AGSD. Further it can have any of theoverhang precursors provided herein.

The nine-nucleoside long 5′-end module containing the miR-122 sequenceused by Chorn et al. (2012) isP-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F)G_(F)U_(F)G_(F). Examples of this 5′-endmodule as modified by AGSD are provided in Table 21A while examples witha higher level of basic nuclease resistance are provided in Table 21B.

Any of the 5′-end nucleosides (P-U_(M)) shown in the examples of agsRNAicompounds in these two tables can be replaced with any of those providedfor herein including where one of the 5′end nucleosides is selected fromthe group consisting of P-G_(F), P-G_(M), P-G_(N), P-G_(L), P-G_(Z),P-G_(H), P-G_(B), P-G_(K), P-G_(Q), P-G_(S), P-G_(T), P-G_(W), P-G_(Y),P-G_(O), P-C_(F), P-C_(M), P-C_(N), P-C_(L), P-C_(Z), P-C_(H), P-C_(B),P-C_(K), P-C_(Q), P-C_(S), P-C_(T), P-C_(W), P-C_(V), P-C_(O), P-U_(F),P-U_(M), P-U_(L), P-U_(Z), P-U_(H), P-U_(B), P-U_(K), P-U_(Q), P-U_(S),P-U_(T), P-U_(W), P-U_(V), P-U_(O), P-T_(L), P-T_(H), 5′-VP-U_(Z),5′-VP-U_(K), 5′-VP-U_(Q), 5′-VP-U_(B), 5′-VP-T_(moe), 5′-VP-T_(E),5′-VP-U_(E), 5′-VP-T_(Z), 5′-VP-T_(K), 5′-VP-T_(Q) and 5′-VP-T_(B).

Any of the nucleosides in Table 21A or 21B with an L modification(s)found in one or more of those in positions 2-9 can have any given L orset of Ls replaced with any of those sugar, sugar analogs or sugarsubstitutes provided for herein for positions 2-19 including one or moreof those independently selected from the group consisting of: S, J, W,V, Q, Y, O, T and cet (i.e., if multiple Ls are replaced the selectedreplacements do not all have to be the same sugar, sugar analog or sugarsubstitute).

Any of the 5′-end modules shown in Table 21A can be used with any seedvehicle shown in Table 19B while any of the 5′-end modules shown inTable 21B can be used with any seed vehicle shown in Table 19C. Furtherany of the resulting compounds can have any of the overhang precursorsprovided for herein.

TABLE 21A Examples of the Application of AGSD to the 5′-end Module formiR-122 used by Chorn et al. (2012) Compositions of Matter Suitable forUse in vitro or in a Subject with a Protective Carrier (5′-3′)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F3)G_(F)U_(F3)G_(F)P-U_(F)G_(F)G_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(F)P-U_(F)G_(L)G_(F)A_(F)G_(L)U_(F)G_(F)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(F)U_(L3)G_(F)U_(F3)G_(F)P-U_(F)G_(L)G_(F)A_(F)G_(L)U_(F3)G_(F)U_(F3)G_(L)P-U_(F)G_(F)G_(L)A_(L)G_(F)U_(F)G_(F)U_(L)G_(F)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F)G_(L)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(L)G_(F)U_(F3)G_(F)U_(L3)G_(F)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F3)G_(L)U_(F3)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(L)U_(F)G_(F)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(L)U_(F3)G_(F)U_(F3)G_(L)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F12)G_(F)U_(F12)G_(F)P-U_(F)G_(F)G_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(F)P-U_(F)G_(L)G_(F)A_(F)G_(L)U_(F)G_(F)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(F)U_(L12)G_(F)U_(F12)G_(F)P-U_(F)G_(L)G_(F)A_(F)G_(L)U_(F12)G_(F)U_(F12)G_(L)P-U_(F)G_(F)G_(L)A_(L)G_(F)U_(F)G_(F)U_(L)G_(F)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F)G_(L)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(L)G_(F)U_(F12)G_(F)U_(L12)G_(F)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F12)G_(L)U_(F12)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(L)U_(F)G_(F)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(L)U_(F12)G_(F)U_(F12)G_(L)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F18)G_(F)U_(F18)G_(F)P-U_(F)G_(F)G_(L)A_(F)G_(F)U_(L)G_(F)U_(F)G_(F)P-U_(F)G_(L)G_(F)A_(F)G_(L)U_(F)G_(F)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(F)U_(L18)G_(F)U_(F18)G_(F)P-U_(F)G_(L)G_(F)A_(F)G_(L)U_(F18)G_(F)U_(F18)G_(L)P-U_(F)G_(F)G_(L)A_(L)G_(F)U_(F)G_(F)U_(L)G_(F)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F)G_(L)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(L)G_(F)U_(F18)G_(F)U_(L18)G_(F)P-U_(F)G_(F)G_(F)A_(F)G_(F)U_(F18)G_(L)U_(F18)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(L)U_(F)G_(F)U_(F)G_(L)P-U_(F)G_(F)G_(L)A_(F)G_(L)U_(F18)G_(F)U_(F18)G_(L)

TABLE 21B Examples of the Application of AGSD to the 5′-end Module formiR-122 used by Chorn et al. (2012) as Adjusted for Use in Subjects withor without a Protective Carrier Compositions of Matter Suitable forAdministration to a Subject with or without a Protective Carrier and forAny Other use as Provided for Herein (5′-3′)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F3)~G_(M)U_(F3)~G_(M)P-U_(M)~G_(F)~G_(M)A_(L)~G_(M)U_(F)~G_(M)U_(L)~G_(M)P-U_(M)~G_(L)~G_(M)A_(F)~G_(L)U_(F)~G_(M)U_(F)~G_(L)P-U_(M)~G_(F)~G_(M)A_(L)~G_(M)U_(F3)~G_(M)U_(L3)~G_(M)P-U_(M)~G_(L)~G_(M)A_(F)~G_(L)U_(F3)~G_(M)U_(F3)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(L)U_(F)~G_(M)U_(F)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F)~G_(L)U_(F)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(L)U_(F3)~G_(M)U_(F3)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F3)~G_(L)U_(F3)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F)~G_(M)U_(F)~G_(M)P-U_(M)~G_(F)~G_(L)A_(F)~G_(M)U_(L)~G_(M)U_(F)~G_(M)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F)~G_(M)U_(F)~G_(M)P-U_(M)~G_(F)~G_(L)A_(F)~G_(M)U_(L3)~G_(M)U_(F3)~G_(M)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F12)~G_(M)U_(F12)~G_(M)P-U_(M)~G_(F)~G_(M)A_(L)~G_(M)U_(F)~G_(M)U_(L)~G_(M)P-U_(M)~G_(L)~G_(M)A_(F)~G_(L)U_(F)~G_(M)U_(F)~G_(L)P-U_(M)~G_(F)~G_(M)A_(L)~G_(M)U_(F12)~G_(M)U_(L12)~G_(M)P-U_(M)~G_(L)~G_(M)A_(F)~G_(L)U_(F12)~G_(M)U_(F12)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(L)U_(F)~G_(M)U_(F)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F)~G_(L)U_(F)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(L)U_(F12)~G_(M)U_(F12)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F12)~G_(L)U_(F12)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(M)U_(L)~G_(M)U_(F)~G_(M)P-U_(M)~G_(F)~G_(L)A_(F)~G_(M)U_(L12)~G_(M)U_(F12)~G_(M)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F18)~G_(M)U_(F18)~G_(M)P-U_(M)~G_(F)~G_(M)A_(L)~G_(M)U_(F)~G_(M)U_(L)~G_(M)P-U_(M)~G_(L)~G_(M)A_(F)~G_(L)U_(F)~G_(M)U_(F)~G_(L)P-U_(M)~G_(F)~G_(M)A_(L)~G_(M)U_(F18)~G_(M)U_(L18)~G_(M)P-U_(M)~G_(L)~G_(M)A_(F)~G_(L)U_(F18)~G_(M)U_(F18)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(L)U_(F)~G_(M)U_(F)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F)~G_(L)U_(F)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(L)U_(F18)~G_(M)U_(F18)~G_(L)P-U_(M)~G_(F)~G_(M)A_(F)~G_(M)U_(F18)~G_(L)U_(F18)~G_(L)P-U_(M)~G_(F)~G_(L)A_(F)~G_(M)U_(L)~G_(M)U_(F)~G_(M)P-U_(M)~G_(F)~G_(L)A_(F)~G_(M)U_(L18)~G_(M)U_(F18)~G_(M)

The following examples are provided to illustrate certain embodiments ofthe invention. They are not intended to limit the invention in any way.

Example I Applications for ags-IMiRs

MiRNAs have been shown to have wide ranging effects on gene expression.In certain instances, these effects are detrimental and related tocertain pathologies. Accordingly, specific miRNA inhibitors which targetsuch miRNAs for degradation are highly desirable. The present inventorhas devised strategies for the synthesis of miRNA inhibitors (agslMiRs)suitable for in vivo delivery which exhibit enhanced stability, theability to form active RNAi triggers in cells, which act in turn toinhibit the activity of endogenous miRNAs associated with disease. Thesedesign paradigms and the resulting miRNA inhibitors are described hereinabove.

Table 22 provides a listing of some of the medical uses of the ags-IMiRsdirected to the indicated miRNAs. The methods of the present invention,however, can be used to generate ags-IMiRs against any miRNA. Methodsfor administration of the oligos of the invention are provided in detailabove.

TABLE 22 MICRORNA TARGETS FOR INHIBITION BY ags-IMiRs AND COMMERCIALAPPLICATIONS MicroRNA Medical Conditions to be Treated using the Targetsags-IMiR Compounds of the Invention miR-24 Treat cancer includinghormone resistant prostate miR-29a Inhibit pathologic apoptosisincluding that due to ischemia reperfusion injury such as occurs afterthe removal of a clot miR-29b Inhibit pathologic apoptosis miR-29cInhibit pathologic apoptosis including that due to ischemia reperfusioninjury such as occurs after the removal of a clot miR-33 Raise goodcholesterol (HDL) levels miR-34a Myocardial infarction miR-122 HepatitisC miR-155 Arthritis; Autoimmune inflammation including that associatedwith cystic fibrosis; Atopic dermatitis miR-208a Chronic heart failure

Elevated levels of miR-21, for example, occur in numerous cancers whereit promotes oncogenesis at least in part by preventing the translationand accumulation of PDCD4. Another example is miR-122 a liver specificmiRNA that promotes replication of the hepatitis C virus.

Compared to antisense oligos that engender catalytic activity againsttheir targets, such as those that are RNase H dependent, the antisenseoligos that function as competitive inhibitors must be used atsubstantially higher concentrations. In vivo various tissues take upoligos in widely ranging amounts. For example, liver and kidney take uprelatively large amounts while resting lymphocytes, testis, skeletalmuscle the CNS and other tissues take up much smaller amounts. Further,antisense oligos that have a competitive inhibitor function have beenshown to perform poorly in tissues that do not avidly take up oligos.Therefore, it would be highly desirable to have oligonucleotide basedmiRNA inhibitors that have a catalytic activity against such targets sothat a wider range of tissues types can be subject to efficient miRNAinhibition. The present invention provides a solution to this pressingneed.

Example II Examples of Applications for miRNA Mimics

Table 23 below provides a listing of miRNAs for which examples ofspecific ss-MiRcompounds have been provided herein. The methods of thepresent invention can be used to mimic any endogenous miRNA, to improveon the mRNA type silencing pattern of an endogenous miRNA for commercialpurposes and can be used to generate designer novel miRNA-likecompounds.

TABLE 23 MICRORNAS MIMICKED BY ags-MiRs AND COMMERCIAL APPLICATIONSMicroRNA Mimicked Medical Conditions to be Treated using the ags-MiR byss-MiR Compounds of the Invention Let-7i and Cancer Let-7 familygenerally miR-24-1 Ischemia reperfusion injury including that associatedwith myocardial infarction; Cardiac fibrosis; Diabetes miR-24-2 Ischemiareperfusion injury including that associated with myocardial infarction;Cardiac fibrosis; Diabetes miR-26a-1 Cancer including liver, head andneck, breast miR-26a-2 Cancer including liver, head and neck, breastmiR-29a Fibrosis including liver, lung, kidney and heart; Systemicsclerosis; Cancers including lung, liver, chronic lymphocytic leukemia;Osteoporosis; Systemic sclerosis; miR-29b-1 Fibrosis including liver,lung, kidney and heart; Systemic sclerosis; Cancers including lung,liver, colon breast, chronic lymphocytic leukemia, acute myeloidleukemia miR-29b-2 Fibrosis including liver, lung, kidney and heart;Systemic sclerosis; Cancers including lung, liver, colon, breast,rhabdomyosarcoma, chronic lymphocytic leukemia, acute myeloid leukemia;miR-29c Fibrosis including liver, lung, kidney and heart; Systemicsclerosis; Cancers including lung, liver, rhabdomyosarcoma, chroniclymphocytic leukemia; miR-34a Cancer including prostate, ovarian,non-small cell lung cancer, pancreatic cancer, stomach cancer,retinoblastoma and chronic lymphocytic leukemia; miR-34b Cancerincluding prostate, ovarian, non-small cell lung cancer, pancreaticcancer, stomach cancer, retinoblastoma and chronic lymphocytic leukemia;miR-34c Cancer including prostate, ovarian, non-small cell lung cancer,pancreatic cancer, stomach cancer, retinoblastoma and chroniclymphocytic leukemia; miR-122 Cancer including liver, lung and cervical;miR-146a Atherosclerosis miR-203 Sensitize cancers with mutant p53including colon cancer to chemotherapy including taxanes miR-214 Nerveregeneration; Diabetes including type 2; miR-499 Myocardial infarctionincluding the ischemia-reperfusion injury related to reversing vesselocclusion;

It is now well established that post-transcriptional gene silencing(PTGS) by miRNA and other RNAi-associated pathways represents anessential layer of complexity to gene regulation. Gene silencing usingRNAi additionally demonstrates huge potential as a therapeutic strategyfor eliminating gene expression associated with the pathology underlyinga number of different disorders.

A number of conventional miRNA compounds closely based on theirendogenous miRNA counterparts are provided herein as putativetherapeutic agents. Cancer is one area of focus since it has been foundthat several different miRNAs are expressed at very low levels in cancercells compared to their normal counterparts. Further, it has been shownthat replacing these miRNAs can have profound anticancer effects.Several specific examples are provided in the Table.

The miRNA mimics provided should also be effective in cell culture invitro. They can be tested in single stranded form as described above orin the presence of a passenger strand, also described in detail above.In this approach, the first strand can be transfected into the targetcells following by subsequent transfection of the second strand after acertain time frame has elapsed. This method should facilitate drugdiscovery efforts, target validation and also provide the means toreduce or eliminate any undesirable off target effects.

While certain of the preferred embodiments of the present invention havebeen described and specifically exemplified above, it is not intendedthat the invention be limited to such embodiments. Various modificationsmay be made thereto without departing from the scope and spirit of thepresent invention, as set forth in the following claims.

1. A single strand oligoribonucleotide ags-siRNA or ags-IMiR compoundfor modulating the expression and/or function of at least one targetnucleic acid sequence expressed in a cell, comprising: a) a nucleosidein position 1 and an associated linkage with the nucleoside in position2 comprising modifications that promote binding of the compound to anargonaute protein; and b) 19 nucleosides operably linked to said firstnucleoside, said nucleosides comprising modifications in positions 2-19that increase nuclease resistance; wherein at least 4 AGSD modificationsare present; c) 1, 2, 3, or 4 optional overhang precursor units; and d)a region of complementary base pairing with the target nucleic acid thatis at least 15 consecutive nucleosides in length beginning at position 2and extending at least through position 16; wherein the compoundexhibits a maximal plateau level of activity in a dose response curveagainst the target that constitutes at least a 50% change in expressionand/or function of the target and said level of change in activity is atleast 20 percentage points greater than the maximal level of activityobtained using an ssRNAi which lacks said AGSD modifications of the samesequence and same 5′end moiety, if any.
 2. A method for modulatingexpression and or function of a target nucleic acid in a target cellcomprising administration of an effective amount of the compound ofclaim 1 wherein said ags-siRNA is directed to a target selected from thegroup consisting of pre-mRNA, mRNA, lncRNA, promoter associated RNA,enhancer RNA, snoRNA, piRNA, xiRNA, sdRNA, moRNA, MSY-RNA, tel-sRNA,crasiRNA, endogenous antisense RNA, a promoters, an enhancers and asuppressors.
 3. The method of claim 2, wherein expression and orfunction of an miRNA target is modulated and said compound is anags-IMiR.
 4. The method of claim 2 wherein said target cells areselected from the group consisting of a cell line; a tissue sample froman organ, gland or neoplastic growth; an enriched sample of parenchymalcells from an organ, gland or neoplastic growth; epithelial tissueincluding simple, stratified, pseudostratified and transitionalepithelium; connective tissues, reticular, adipose, blood and lymphoidtissues; of nervous tissue isolated from brain, spinal cord, ganglion,and nerve and, neuronal cells, glial cells, skeletal muscle cells,cardiac muscle cells and smooth muscle cells.
 5. The compound of claim 1wherein said the nucleoside in position 1 and the associated linkagewith the nucleoside in position 2 promote binding of the compound to anargonaute protein and comprise one or more sugar modificationsconsisting of 2′-fluoro, 2′-O-methyl, 2′-methoxyethyl, 2′-deoxyribose,LNA, FANA, 4'S-FANA, ALN, AENA, CENA, HM, HNA, EA, F-CeNA, CeNA, UNA,CRN R monomer and CRN Q monomer and one or more linkage modificationsselected from phosphodiester, phosphorothioate, N3′ phosphoramidate andamide.
 6. The compound of claim 1 wherein said overhang precursor unitsare selected from the group consisting of ˜GL˜UL˜UX, ˜UL˜UL˜UX,˜CL˜UL˜UX, ˜GL˜CL˜UX, ˜AL˜GL˜UX, ˜AL˜GL˜CX, ˜AL˜AL˜AX, ˜AL˜GL˜AX,˜GL˜AL˜AX, ˜CL˜GL˜CX, ˜GL˜GL˜CX and ˜GL˜GL˜UX where the subscriptsrepresent sugar modifications indicated by L are selected from the groupconsisting of L, F, J, W, V, Y, T, TL and I and the modificationsindicated by X are selected from the group consisting of ribose,2′-fluoro, or 2′-O-methyl.
 7. The compound of claim 6 wherein saidoverhang precursors are linked to the nucleoside in position 19 and toeach other by a linkage selected from the group consisting ofphosphodiester, phosphorothioate, N3′ phosphoramidate and amide.
 8. Themethod of claim 2 wherein said compound and comparator ssRNAi aredelivered to a cell line or a primary parenchymal cell in vitro via amethod selected from the group consisting of transfection,electroporation and gymnosis.
 9. The compound of claim 1 wherein saidcompound and comparator ssRNAi comprise an enveloping protectivecarrier.
 10. The compound of claim 9 wherein said nuclease resistance isachieved via inclusion of one or more modifications consisting of: a)all of the nucleosides in positions 2-19 are 2′-fluoro and all of thelinkages phosphodiester; b) nucleosides in positions 2-19 are 2′-fluoroalternated with 2′-O-methyl nucleosides with the 2′-fluoro being in theeven numbered positions, c) inclusion of a 2′-O-methyl modification atnucleoside position 2 and two contiguous nucleosides in the regiondefined by positions 3-13 have a 2′-fluoro modified sugar so that whenthe alternating pattern of single 2′-O-methyl with single 2′-fluoromodified sugar is continued the 2′-fluoro modification will fall onnucleoside positions 14 and 16; d) inclusion of a ribose or HM atposition 14 and optionally at position 16; and e) inclusion ofphosphorothioate linkages at sites 2-3, and an overhang precursor wherethe units are linked to each other and to nucleoside 19 byphosphorothioates.
 11. The method of claim 2 wherein said compound andcomparator ssRNAi are administered to cells in a subject without anenveloping protective carrier.
 12. The method of claim 11 wherein saidnuclease resistance is achieved via inclusion of 2′-fluoro alternatingwith 2′-O-methyl nucleosides in positions 2-19 with the 2′-fluoro beingin the even numbered positions where phosphorothioate linkages occurbetween nucleoside positions 2-3, 4-5, 6-7, 8-9, 10-11, 12-13, 14-15,15-16, 16-17, 17-18 and 18-19 with phosphodiester linkages in positions3-4, 5-6, 7-8, 9-10, 11-12 and 13-14.
 13. The method of claim 11 whereinsaid nuclease resistance is achieved via inclusion of a 3 or 4 unitoverhang precursor where the units are linked by phosphorothioatelinkages to each other and to the nucleoside in position 19 and optionalphosphorothioate linkages between nucleoside positions 2-3, 4-5, 6-7,8-9, 10-11, 12-13, 14-15, 16-17, 17-18 and 18-19 with phosphodiesterlinkages in positions 3-4, 5-6, 7-8, 9-10, 11-12, 13-14 and 15-16. 14.The method of claim 2 wherein said AGSD modifications are selected froma group consisting of LNA, HNA, ANA, CRN R monomer, CRN Q monomer, HM,FHNA, CeNA, F-CeNA, cEt, 2-thiouracil, 4-thiouracil, pseudouracil and5-methyluracil.
 15. An in vitro method of improving an RNAi effect invitro or in vivo against a target nucleic acid, said method comprising;(i) obtaining an oligoribonucleotide sequence which specificallyhybridizes to said target nucleic acid; (ii) introducing one or moreaccommodating guide strand design (AGSD) modifications and otherchemical modifications into said oligoribonucleotide, thereby producinga modified oligoribonucleotide, wherein said modifications are effectiveto modulate at least one parameter selected from the group consisting ofa) enhanced resistance to 5′ and 3′ exonucleases and endonucleases invivo; b) enhanced formation of a C3′-endo conformation in one or moreflexible sugar moieties in said oligoribonucleotide strand comprisingsaid AGSD modifications; c) increased potency in vivo and in vitro; d)reduced steric hinderance of strand interaction with RISC machinery viaomission of moieties which project into major or minor grooves ofduplexed RNAi triggers while maintaining RNAi activity; e) reducedoff-target effects; and f) enhanced activity of the RNAi mechanismwithin target tissue in vivo relative to RNA strands lacking said AGSDmodifications; and (iii) contacting a first population of cellsexpressing said target nucleic acid with the modifiedoligoribonucleotide of step ii) and a second population of identicalcells expressing said target nucleic acid with an identicaloligoribonucleotide strand lacking said modifications; and; (iv)determining the effect of said contact of step iii) on said parameter,parameters being affected by those strands comprising said AGSDmodifications being identified as AGSD modifications which improve RNAieffects in vitro and in vivo.